WO2022204274A1 - Anti-tmem106b antibodies for treating and preventing coronavirus infections - Google Patents
Anti-tmem106b antibodies for treating and preventing coronavirus infections Download PDFInfo
- Publication number
- WO2022204274A1 WO2022204274A1 PCT/US2022/021533 US2022021533W WO2022204274A1 WO 2022204274 A1 WO2022204274 A1 WO 2022204274A1 US 2022021533 W US2022021533 W US 2022021533W WO 2022204274 A1 WO2022204274 A1 WO 2022204274A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- seq
- nos
- antibody
- tmem106b
- antibodies
- Prior art date
Links
- 208000001528 Coronaviridae Infections Diseases 0.000 title claims description 34
- 102100026232 Transmembrane protein 106B Human genes 0.000 claims abstract description 117
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 48
- 241000711573 Coronaviridae Species 0.000 claims abstract description 48
- 101000834926 Homo sapiens Transmembrane protein 106B Proteins 0.000 claims abstract description 27
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 119
- 238000000034 method Methods 0.000 claims description 91
- 230000027455 binding Effects 0.000 claims description 87
- 239000008194 pharmaceutical composition Substances 0.000 claims description 39
- -1 TM-2 Chemical compound 0.000 claims description 37
- 230000000120 cytopathologic effect Effects 0.000 claims description 37
- 150000001413 amino acids Chemical class 0.000 claims description 34
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 30
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 30
- 239000012634 fragment Substances 0.000 claims description 29
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 230000010076 replication Effects 0.000 claims description 13
- 230000005540 biological transmission Effects 0.000 claims description 7
- 230000001086 cytosolic effect Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 claims description 4
- 238000013519 translation Methods 0.000 claims description 4
- 102000003839 Human Proteins Human genes 0.000 claims description 3
- 108090000144 Human Proteins Proteins 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 abstract description 10
- 210000004027 cell Anatomy 0.000 description 143
- 101710175911 Transmembrane protein 106B Proteins 0.000 description 108
- 235000001014 amino acid Nutrition 0.000 description 95
- 238000006467 substitution reaction Methods 0.000 description 83
- 108090000765 processed proteins & peptides Proteins 0.000 description 73
- 239000000427 antigen Substances 0.000 description 71
- 102000036639 antigens Human genes 0.000 description 70
- 108091007433 antigens Proteins 0.000 description 70
- 102000004196 processed proteins & peptides Human genes 0.000 description 62
- 229920001184 polypeptide Polymers 0.000 description 59
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 44
- 229940024606 amino acid Drugs 0.000 description 35
- 230000035772 mutation Effects 0.000 description 30
- 239000013598 vector Substances 0.000 description 30
- 201000010099 disease Diseases 0.000 description 27
- 150000007523 nucleic acids Chemical class 0.000 description 25
- 108020004707 nucleic acids Proteins 0.000 description 24
- 102000039446 nucleic acids Human genes 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- 125000000539 amino acid group Chemical group 0.000 description 19
- 230000003833 cell viability Effects 0.000 description 19
- 102000005962 receptors Human genes 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- 108010087819 Fc receptors Proteins 0.000 description 17
- 102000009109 Fc receptors Human genes 0.000 description 17
- 241000700605 Viruses Species 0.000 description 17
- 208000035475 disorder Diseases 0.000 description 17
- 102000051691 human TMEM106B Human genes 0.000 description 17
- 238000005516 engineering process Methods 0.000 description 16
- 230000006870 function Effects 0.000 description 16
- 230000002401 inhibitory effect Effects 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 238000003780 insertion Methods 0.000 description 15
- 230000037431 insertion Effects 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 230000004048 modification Effects 0.000 description 15
- 238000012986 modification Methods 0.000 description 15
- 108060003951 Immunoglobulin Proteins 0.000 description 14
- 102000018358 immunoglobulin Human genes 0.000 description 14
- 238000012217 deletion Methods 0.000 description 13
- 230000037430 deletion Effects 0.000 description 13
- 210000004408 hybridoma Anatomy 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 230000013595 glycosylation Effects 0.000 description 10
- 238000006206 glycosylation reaction Methods 0.000 description 10
- 238000000338 in vitro Methods 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 241000282412 Homo Species 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000010367 cloning Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000012636 effector Substances 0.000 description 9
- 230000004927 fusion Effects 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 208000025721 COVID-19 Diseases 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 238000003127 radioimmunoassay Methods 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 230000009870 specific binding Effects 0.000 description 8
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 7
- 210000004899 c-terminal region Anatomy 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 210000002919 epithelial cell Anatomy 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 239000007790 solid phase Substances 0.000 description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 208000037847 SARS-CoV-2-infection Diseases 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 230000004075 alteration Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 102000025171 antigen binding proteins Human genes 0.000 description 6
- 108091000831 antigen binding proteins Proteins 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 6
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 230000008685 targeting Effects 0.000 description 6
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 5
- 241000699800 Cricetinae Species 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 201000011240 Frontotemporal dementia Diseases 0.000 description 5
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 5
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 101100368627 Mus musculus Tmem106b gene Proteins 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 150000001720 carbohydrates Chemical group 0.000 description 5
- 235000018417 cysteine Nutrition 0.000 description 5
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 210000003712 lysosome Anatomy 0.000 description 5
- 230000001868 lysosomic effect Effects 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 238000002823 phage display Methods 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 230000004481 post-translational protein modification Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 230000029812 viral genome replication Effects 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 4
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 4
- 241000282693 Cercopithecidae Species 0.000 description 4
- 108091035707 Consensus sequence Proteins 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 241000288906 Primates Species 0.000 description 4
- 239000004473 Threonine Substances 0.000 description 4
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 210000001163 endosome Anatomy 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 210000003292 kidney cell Anatomy 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 150000002482 oligosaccharides Chemical class 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 210000004988 splenocyte Anatomy 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 241000282552 Chlorocebus aethiops Species 0.000 description 3
- 241000494545 Cordyline virus 2 Species 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 244000309467 Human Coronavirus Species 0.000 description 3
- 108010015268 Integration Host Factors Proteins 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 3
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 3
- 230000004988 N-glycosylation Effects 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 229940049595 antibody-drug conjugate Drugs 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000003752 polymerase chain reaction Methods 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 208000031504 Asymptomatic Infections Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 description 2
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 206010063629 Hippocampal sclerosis Diseases 0.000 description 2
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 2
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 231100000070 MTS assay Toxicity 0.000 description 2
- 238000000719 MTS assay Methods 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 2
- 230000004989 O-glycosylation Effects 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 241000315672 SARS coronavirus Species 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 101000980463 Treponema pallidum (strain Nichols) Chaperonin GroEL Proteins 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 244000000188 Vaccinium ovalifolium Species 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000008228 bacteriostatic water for injection Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 2
- 238000002983 circular dichroism Methods 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 239000012149 elution buffer Substances 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000015389 hippocampal sclerosis of aging Diseases 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 238000000111 isothermal titration calorimetry Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000001985 kidney epithelial cell Anatomy 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 238000002818 protein evolution Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000012146 running buffer Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 210000002845 virion Anatomy 0.000 description 2
- KYBXNPIASYUWLN-WUCPZUCCSA-N (2s)-5-hydroxypyrrolidine-2-carboxylic acid Chemical compound OC1CC[C@@H](C(O)=O)N1 KYBXNPIASYUWLN-WUCPZUCCSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 1
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 1
- 102100033400 4F2 cell-surface antigen heavy chain Human genes 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- 102100021266 Alpha-(1,6)-fucosyltransferase Human genes 0.000 description 1
- 241000004176 Alphacoronavirus Species 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 102000043334 C9orf72 Human genes 0.000 description 1
- 108700030955 C9orf72 Proteins 0.000 description 1
- 101150014718 C9orf72 gene Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000028399 Critical Illness Diseases 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102100024233 High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A Human genes 0.000 description 1
- 101000800023 Homo sapiens 4F2 cell-surface antigen heavy chain Proteins 0.000 description 1
- 101000819490 Homo sapiens Alpha-(1,6)-fucosyltransferase Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101001117267 Homo sapiens High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- 241000482741 Human coronavirus NL63 Species 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 240000002769 Morchella esculenta Species 0.000 description 1
- 235000002779 Morchella esculenta Nutrition 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 241000238413 Octopus Species 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000001825 Polyoxyethene (8) stearate Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 102000019204 Progranulins Human genes 0.000 description 1
- 108010012809 Progranulins Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710150114 Protein rep Proteins 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101710152114 Replication protein Proteins 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102100040347 TAR DNA-binding protein 43 Human genes 0.000 description 1
- 101710150875 TAR DNA-binding protein 43 Proteins 0.000 description 1
- 208000036278 TDP-43 proteinopathy Diseases 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 101150117115 V gene Proteins 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 102000018265 Virus Receptors Human genes 0.000 description 1
- 108010066342 Virus Receptors Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000009824 affinity maturation Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 1
- 238000010913 antigen-directed enzyme pro-drug therapy Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940052143 bamlanivimab Drugs 0.000 description 1
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 1
- 229950000971 baricitinib Drugs 0.000 description 1
- 208000013404 behavioral symptom Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000012575 bio-layer interferometry Methods 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940051183 casirivimab Drugs 0.000 description 1
- 230000034303 cell budding Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000002967 competitive immunoassay Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000009459 flexible packaging Methods 0.000 description 1
- 238000005206 flow analysis Methods 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 230000033581 fucosylation Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 201000001451 hypomyelinating leukodystrophy Diseases 0.000 description 1
- 229940051184 imdevimab Drugs 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 210000001739 intranuclear inclusion body Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000036546 leukodystrophy Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 230000034217 membrane fusion Effects 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000010399 physical interaction Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001583 poly(oxyethylated polyols) Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 238000002702 ribosome display Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 230000007502 viral entry Effects 0.000 description 1
- 230000006490 viral transcription Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000010464 virion assembly Effects 0.000 description 1
- 230000010463 virion release Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- the present disclosure relates to uses of anti-TMEM106B antibodies for treating and preventing coronavirus (e.g., SARS-CoV-2) infections.
- coronavirus e.g., SARS-CoV-2
- Transmembrane protein 106B is a type 2 single pass transmembrane glycoprotein residing primarily within the membrane of late endosome and lysosomes.
- TMEM106B is highly conserved in mammals, with the human protein sharing 99% sequence identity with the cynomolgus variant and 97% sequence identify with the murine ortholog.
- TMEM106B has a cytoplasmic domain predicted to range from amino acid residues 1-92 (of human TMEM106B; SEQ ID NO: 1), a transmembrane domain predicted to range from amino acid residues 96-117, and a luminal domain predicted to range from amino acid residues 118-274.
- Five sequence motifs of post-translational N-glycosylation sites (N-X-T/S) span its luminal domain.
- Simple glycans are added to three of the asparagine residues (N145, N151, and N164) and are not critical for TMEM106B localization.
- TMEM106B Complex glycans are added to the most C-terminal motifs atN183 andN256; loss of complex glycans on N 183 impairs TMEM106B forward transport to endosomes/lysosomes and results in endoplasmic retention. Additionally, N256 complex glycosylation is necessary for proper TMEM106B sorting. (See, e.g., Nicholson and Rademakers, 2016, Acta Neuropathol, 132:639-651.) [0006] The function of TMEM106B has not been fully characterized. Recent reports have indicated a role of TMEM106B in lysosomal function and maintenance by inhibiting trafficking of lysosomes along dendrites.
- TMEM106B has been identified as a host factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Genetic deletion of TMEM106B reduced SARS-CoV-2 coronavirus replication and infection (Baggen et al, 2021, Nature Genetics, doi.org/i0.I038/s41588-021-00805-2; Baggen et al, 2020, bioRxiv, doi:10.1101/2020.09.28.316281; Wang et al, 2020, bioRxiv, doi: 10.1101/2020/09.24.312298; Wang etal, 2021, Cell, 184:1-14).
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- the present disclosure is generally directed to methods of treating, preventing, or reducing the risk of coronavirus (e.g., SARS-CoV-2) infection comprising administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to TMEM106B.
- coronavirus e.g., SARS-CoV-2
- the anti-TMEM106 antibody for uses and methods as provided herein has a property selected from the group consisting of: reducing coronavirus replication, reducing coronavirus transmission, reducing coronavirus genome translation, reducing coronavirus cell entry, reducing coronavirus release from an infected cell, and any combination thereof.
- the antibody reduces a cytopathic effect in a cell infected with SARS- CoV-2, optionally wherein the cell is a VeroE6 cells or a NCI-H1975 cell.
- TMEM106B antibody for use in treating, preventing, or reducing the risk of coronavirus infection
- the anti-TMEM106B antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM- 34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46,
- the anti-TMEM106B antibody comprises the six HVRs (e.g., as shown in Tables 1-4 below) of the antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM- 28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-
- TMEM106B antibody for use in treating, preventing, or reducing the risk of coronavirus infection which binds essentially the same TMEM106B epitope as a reference anti-TMEM106B antibody comprising the VH and VL (e.g., as shown in Tables 5 and 6 below) of the antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM- 27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-
- TMEM106B antibody for use in treating, preventing, or reducing the risk of coronavirus infection, wherein the antibody competitively inhibits the binding to TMEM106B of an antibody comprising the heavy chain variable region and the light chain variable region of any of the antibodies selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM- 16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM
- the antibody binds a truncated TMEM106B protein comprising amino acids 122-210 of SEQ ID NO: 1.
- the antibody is in Bin 2.
- the antibody is in Bin 3.
- the antibody is in Bin 4.
- the antibody is not in Bin 5.
- the antibody is not in Bin 1.
- the antibody is a monoclonal antibody. In some embodiments that may be combined with any of the embodiments provided herein, the antibody is of the IgG class, the IgM class, or the IgA class. In some embodiments, the antibody is of the IgG class and has an IgGl, IgG2, or IgG4 isotype. In certain embodiments that may be combined with any of the embodiments provided herein, the anti-TMEM106B antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human TMEM106B or a mammalian TMEM106B protein.
- the fragment is a Fab, Fab’, Fab’-SH, F(ab’)2, Fv, or scFv fragment.
- the anti-TMEM106B antibody is a full-length antibody.
- the antibody is a humanized antibody or a chimeric antibody.
- Other aspects of the present disclosure relate to a pharmaceutical composition comprising an anti-TMEM106B antibody of any of the preceding embodiments, and a pharmaceutically acceptable carrier.
- an anti-TMEM106B antibody of any of the embodiments herein in the manufacture of a medicament for treating, preventing, or reducing the risk of coronavirus (e.g., SARS-CoV-2) infection.
- coronavirus e.g., SARS-CoV-2
- FIG. 1 sets forth data showing the effect of anti-TMEM106B antibodies of the present disclosure on cell survival following SARS-CoV-2 infection of VeroE6 African green monkey kidney epithelial cells.
- FIGS. 2A, 2B, 2C, 2D, 2E, and 2F set forth data showing the effect of anti-TMEM106B antibodies of the present disclosure on cell viability following SARS-CoV-2 infection ofNCI-H1975 human lung epithelial cells.
- FIGS. 3A, 3B, 3C, and 3D set forth data showing a dose tritration effect of anti-TMEM106B antibodies of the present disclosure on cell viability following SARS-CoV-2 infection ofNCI-H1975 human lung epithelial cells.
- DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE [0021] The present disclosure relates to the use of anti-TMEM106B antibodies (e.g., monoclonal antibodies), and pharmaceutical compositions thereof, for treating, preventing, or reducing the risk of coronavirus infection.
- methods are provided herein for treating, preventing, or reducing the risk of coronavirus infection by administering to an individual in need thereof an anti-TMEM106B antibody.
- TMEM106B or “TMEM106B polypeptide” are used interchangeably herein refer herein to any native TMEM106B from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)) and rodents (e.g., mice and rats), unless otherwise indicated.
- mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)
- rodents e.g., mice and rats
- the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses "full- length," unprocessed TMEM106B as well as any form of TMEM106B that results from processing in the cell. In some embodiments, the TMEM106B is human TMEM106B. In some embodiments, the amino acid sequence of an exemplary TMEM106B is Uniprot Accession No: Q9NUM4 as of June 27, 2006. In some embodiments, the amino acid sequence of an exemplary human TMEM106B is SEQ ID NO: 1.
- anti-TMEM106B antibody an “antibody that binds to TMEM106B,” and “antibody that specifically binds TMEM106B” refer to an antibody that is capable of binding TMEM106B with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting TMEM106B.
- the extent of binding of an anti-TMEM106B antibody to an unrelated, non-TMEM106B polypeptide is less than about 10% of the binding of the antibody to TMEM106B as measured, e.g., by a radioimmunoassay (RIA).
- RIA radioimmunoassay
- an antibody that binds to TMEM106B has a dissociation constant (KD) of ⁇ 1 mM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 8 M or less, e.g. from 10 8 M to 10 13 M, e.g., from 10 9 Mto 10 13 M).
- KD dissociation constant
- an anti-TMEM106B antibody binds to an epitope of TMEM106B that is conserved among TMEM106B from different species.
- the term “specific binding” or “specifically binds” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction.
- Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target.
- telomere binding or “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a KD for the target of about any of 10 4 M or lower, 10 5 M or lower, 10 6 M or lower, 10 7 M or lower, 10 8 M or lower, 10 9 M or lower, 10 10 M or lower, 10 11 M or lower, 10 12 M or lower or a KD in the range of 10 4 M to 10 6 M or 10 6 M to 10 10 M or 10 7 M to 10 9 M.
- affinity and KD values are inversely related.
- binding refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
- immunoglobulin (Ig) is used interchangeably with “ antibody ” herein.
- antibody immunoglobulin
- antibody herein is used in the broadest sense and specially covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) including those formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
- Native antibodies are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical Light (“L”) chains and two identical heavy (“H”) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intra-chain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
- VH variable domain
- Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains.
- the light chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (“K”) and lambda (“l”), based on the amino acid sequences of their constant domains.
- immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated alpha (“ot”), delta (“d”), epsilon (“e”), gamma (“g”), and mu ( m ). respectively.
- the g and a classes are further divided into subclasses (isotypes) on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
- subclasses immunoglobulins
- the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. , Cellular and Molecular Immunology, 4 th ed. (W.B. Saunders Co., 2000).
- variable region refers to the amino-terminal domains of the heavy or light chain of the antibody.
- the variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.
- variable refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies, such as anti-TMEM106B antibodies of the present disclosure.
- the variable domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen.
- HVRs hypervariable regions
- FR framework regions
- the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure.
- the HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Rabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)).
- the constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent-cellular toxicity.
- monoclonal antibody refers to an antibody, such as a monoclonal anti-TMEM106B antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e.. the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g., isomerizations, amidations, etc.) that may be present in minor amounts.
- Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
- the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins.
- the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method, recombinant DNA methods, and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.
- full-length antibody “ intact antibody ” or “ whole antibody” are used interchangeably to refer to an antibody, such as an anti-TMEM106B antibody of the present disclosure, in its substantially intact form, as opposed to an antibody fragment.
- whole antibodies include those with heavy and light chains including an Fc region.
- the constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof.
- the intact antibody may have one or more effector functions.
- an “ antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
- antibody fragments include Fab, Fab', F(ab') 2 and Fv fragments; diabodies; linear antibodies ( see U.S. Patent 5641870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 (1995)); single-chain antibody molecules and multispecific antibodies formed from antibody fragments.
- Papain digestion of antibodies produces two identical antigen-binding fragments, called “ Fab ” fragments, and a residual “ Fc ” fragment, a designation reflecting the ability to crystallize readily.
- the Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (V H ), and the first constant domain of one heavy chain (C H I). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen binding site.
- F(ab') 2 antibody fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the C H I domain including one or more cysteines from the antibody hinge region.
- Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group.
- F(ab') 2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
- the Fc fragment comprises the carboxy -terminal portions of both heavy chains held together by disulfides.
- the effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.
- Functional fragments of antibodies comprise a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability.
- antibody fragments include linear antibody, single-chain antibody molecules and multispecific antibodies formed from antibody fragments.
- diabodies refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10) residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the variable domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment having two antigen-binding sites.
- Bispecific diabodies are heterodimers of two “crossover” sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains.
- a “chimeric antibody ” refers to an antibody (immunoglobulin), such as a chimeric anti-TMEM106B antibody of the present disclosure, in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
- an antibody immunoglobulin
- a chimeric anti-TMEM106B antibody of the present disclosure in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another
- Chimeric antibodies of interest herein include PRIMATIZED ® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with an antigen of interest.
- “humanized antibody” is used a subset of “chimeric antibodies.”
- “Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies comprising amino acid residues from non-human HVRs and amino acid residues from human FRs.
- a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g. , CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
- a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
- a "humanized form" of an antibody, e.g., a non-human antibody refers to an antibody that has undergone humanization.
- a “human antibody ” is one that possesses an amino-acid sequence corresponding to that of an antibody, such as an anti-TMEM106B antibody of the present disclosure, produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage- display libraries and yeast-display libraries.
- Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice as well as generated via a human B-cell hybridoma technology.
- hypervariable region. HVR. or HV. when used herein refers to the regions of an antibody-variable domain, such as that of an anti-TMEM106B antibody of the present disclosure, that are hypervariable in sequence and/or form structurally defined loops.
- antibodies comprise six HVRs; three in the VH (HI, H2, H3), and three in the VL (LI, L2, L3).
- H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies.
- Naturally occurring came lid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain.
- the HVRs may be Rabat complementarity-determining regions (CDRs) based on sequence variability and are the most commonly used (Rabat et al., supra).
- the HVRs may be Chothia CDRs. Chothia refers instead to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)).
- the HVRs may be AbM HVRs. The AbM HVRs represent a compromise between the Rabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody-modeling software.
- the HVRs may be “contact” HVRs. The
- contact HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below.
- HVRs may comprise “extended HVRs” as follows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 (HI), 50-65 or 49-65 (a preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) in the VH.
- the variable -domain residues are numbered according to Rabat et al., supra, for each of these extended-HVR definitions.
- Framework or “FR” residues are those variable-domain residues other than the HVR residues as herein defined.
- acceptor human framework is a framework comprising the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework.
- An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may comprise pre-existing amino acid sequence changes. In some embodiments, the number of pre existing amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.
- VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
- a “human consensus framework ” is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.
- the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
- the subgroup of sequences is a subgroup as in Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for the VL, the subgroup may be subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat el al, supra. Additionally, for the VH, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat el a , supra.
- amino-acid modification at a specified position, e.g., of an anti-TMEM106B antibody of the present disclosure, refers to the substitution or deletion of the specified residue, or the insertion of at least one amino acid residue adjacent the specified residue. Insertion “adjacent” to a specified residue means insertion within one to two residues thereof. The insertion may be N-terminal or C-terminal to the specified residue.
- the preferred amino acid modification herein is a substitution.
- An off in i ty-ma i fire cl antibody such as an affinity matured anti-TMEM106B antibody of the present disclosure, is one with one or more alterations in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody that does not possess those alteration(s).
- an affinity-matured antibody has nanomolar or even picomolar affinities for the target antigen.
- Affinity-matured antibodies are produced by procedures known in the art. For example, Marks el al. Bio/T echnology 10:779-783 (1992) describes affinity maturation by VH- and V L -domain shuffling.
- Random mutagenesis of HVR and/or framework residues is described by, for example: Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier etal. Gene 169:147- 155 (1995); Yelton et al. J. Immunol. 155: 1994-2004 (1995); Jackson et al. J. Immunol. 154(7):3310-9 (1995); and Hawkins etal, J. Mol. Biol. 226:889-896 (1992).
- TV is the minimum antibody fragment which comprises a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
- Single-chain Fv also abbreviated as “sFv” or “scFv are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain.
- the sFv polypeptide further comprises a polypeptide linker between the V H and VL domains, which enables the sFv to form the desired structure for antigen binding.
- Antibody effector functions refer to those biological activities attributable to the Fc region
- Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions.
- the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy -chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl- terminus thereof.
- the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.
- composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
- Suitable native-sequence Fc regions for use in the antibodies of the present disclosure include human IgGl, IgG2, IgG3 and IgG4.
- a “ native sequence Fc region ” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature.
- Native sequence human Fc regions include a native sequence human IgGl Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.
- a “ variant Fc region ” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s).
- the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide.
- the variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith.
- he receptor or “ FcR ” describes a receptor that binds to the Fc region of an antibody.
- the preferred FcR is a native sequence human FcR.
- a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII. and FcyRII I subclasses, including allelic variants and alternatively spliced forms of these receptors, FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
- Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (“ITAM”) in its cytoplasmic domain.
- Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (“ITIM”) in its cytoplasmic domain.
- ITAM immunoreceptor tyrosine-based activation motif
- ITIM immunoreceptor tyrosine-based inhibition motif
- Other FcRs including those to be identified in the future, are encompassed by the term “FcR” herein. FcRs can also increase the serum half-life of antibodies.
- percent (%) amino acid sequence identity and “ homology ” with respect to a peptide, polypeptide or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art needed to achieve maximal alignment over the full-length of the sequences being compared.
- compete when used in the context of antibodies (e.g., neutralizing antibodies) that compete for the same epitope means competition between antibody as determined by an assay in which the antibody being tested prevents or inhibits (e.g., reduces) specific binding of a reference molecule (e.g., a ligand, or a reference antibody) to a common antigen (e.g., TMEM106B or a fragment thereof).
- a reference molecule e.g., a ligand, or a reference antibody
- a common antigen e.g., TMEM106B or a fragment thereof.
- RIA solid phase direct or indirect radioimmunoassay
- EIA solid phase direct or indirect enzyme immunoassay
- sandwich competition assay see, e.g., Stahli etal., 1983, Methods in Enzymology 9:242-253
- solid phase direct biotin-avidin EIA see, e.g., Kirkland el al., 1986, 1. Immunol.
- solid phase direct labeled assay solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using 1-125 label (see, e.g., Morel etal., 1988, Molec. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., Cheung, etal., 1990, Virology 176:546-552); and direct labeled RIA (Moldenhauer et al., 1990, Scand. I. Immunol. 32:77-82).
- such an assay involves the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabelled test antibody and a labeled reference antibody.
- Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antibody.
- the test antibody is present in excess.
- Antibodies identified by competition assay include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur. Additional details regarding methods for determining competitive binding are provided below and, in the examples, herein.
- a competing antibody when present in excess, it will inhibit (e.g., reduce) specific binding of a reference antibody to a common antigen by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, and/or near 100%.
- Antibodies that compete for binding to the same region of TMEM106B are considered to be in the same antibody “bin ”
- Exemplary bins of antibodies that bind to TMEM06B are discussed herein, e.g., in Examples 4 and 6.
- an antibody in “ Bin 1 ” refers to an antibody that competes for binding to the same or overlapping TMEM106B region as the TM1, TM17, TM22, TM26, TM79, and/or TM82 antibodies provided herein.
- an antibody in “ Bin 2” refers to an antibody that competes for binding to the same or overlapping TMEM106B region as the TM3, TM9, TM10, TM11, TM12, TM13, TM18, TM19, TM21, TM24, TM25, TM32, TM35, TM37, TM42, TM45, TM48, TM54, TM59, TM60, TM61, and/or TM76 antibodies provided herein.
- an antibody in “ Bin 3 ” refers to an antibody that competes for binding to the same or overlapping TMEM106B region as the TM7, TM15, TM83, and/or TM84 antibodies provided herein.
- an antibody in “ Bin 4 ” refers to an antibody that competes for binding to the same or overlapping TMEM106B region as the TM5, TM28, TM29, TM30, TM63, TM64, TM72, TM78, TM80, TM86, and/or TM88 antibodies provided herein.
- an antibody in “ Bin 5 ” refers to an antibody that does not bind to a truncated TMEM106B comprising amino acids 122-210 of SEQ ID NO: 1.
- an “ interaction ” between a TMEM106B polypeptide and a second polypeptide encompasses, without limitation, protein-protein interaction, a physical interaction, a chemical interaction, binding, covalent binding, and ionic binding.
- an antibody “inhibits interaction” between two polypeptides when the antibody disrupts, reduces, or completely eliminates an interaction between the two polypeptides.
- the interaction can be inhibited by at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, and/or near 100%.
- epitope includes any determinant capable of being bound by an antibody.
- An epitope is a region of an antigen that is bound by an antibody that targets that antigen, and when the antigen is a polypeptide, includes specific amino acids that directly contact the antibody. Most often, epitopes reside on polypeptides, but in some instances, can reside on other kinds of molecules, such as nucleic acids.
- Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three-dimensional structural characteristics, and/or specific charge characteristics.
- antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of polypeptides and/or macromolecules.
- An “ agonist ” antibody or an “ activating ” antibody is an antibody that induces (e.g. , increases) one or more activities or functions of the antigen after the antibody binds the antigen.
- An “ antagonist ” antibody or a “ blocking ” antibody or an “inhibitory” antibody is an antibody that reduces, inhibits, and/or eliminates (e.g., decreases) antigen binding to one or more ligand after the antibody binds the antigen, and/or that reduces, inhibits, and/or eliminates (e.g., decreases) one or more activities or functions of the antigen after the antibody binds the antigen.
- antagonist antibodies, or blocking antibodies, or inhibitory antibodies substantially or completely inhibit antigen binding to one or more ligand and/or one or more activities or functions of the antigen.
- An “ isolated ” antibody such as an isolated anti-TMEM106B antibody of the present disclosure, is one that has been identified, separated and/or recovered from a component of its production environment (e.g., naturally or recombinantly).
- the isolated antibody is free of association with all other contaminant components from its production environment.
- Contaminant components from its production environment such as those resulting from recombinant transfected cells, are materials that would typically interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
- the antibody will be purified: (1) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
- Isolated antibody includes the antibody in situ within recombinant T-cells since at least one component of the antibody’s natural environment will not be present. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step.
- An “isolated” nucleic acid molecule encoding an antibody is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it was produced. Preferably, the isolated nucleic acid is free of association with all components associated with the production environment.
- the isolated nucleic acid molecules encoding the polypeptides and antibodies herein is in a form other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from nucleic acid encoding the polypeptides and antibodies herein existing naturally in cells.
- vector as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
- plasmid refers to a circular double stranded DNA into which additional DNA segments may be ligated.
- phage vector Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome.
- viral vector is capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
- vectors e.g., non-episomal mammalian vectors
- vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
- certain vectors are capable of directing the expression of genes to which they are operatively linked.
- Such vectors are referred to herein as “recombinant expression vectors,” or simply, “expression vectors.”
- expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
- plasmid and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector.
- Polynucleotide refers to polymers of nucleotides of any length, and include DNA and RNA.
- the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction.
- a “host cell ” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts.
- Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation.
- a host cell includes cells transfected in vivo with a polynucleotide(s) of this invention.
- Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
- the term “preventing” includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual.
- An individual may be predisposed to, susceptible to a particular disease, disorder, or condition, or at risk of developing such a disease, disorder, or condition, but has not yet been diagnosed with the disease, disorder, or condition.
- an individual “ at risk ” of developing a particular disease, disorder, or condition may or may not have detectable disease or symptoms of disease, and may or may not have displayed detectable disease or symptoms of disease prior to the treatment methods described herein.
- At risk denotes that an individual has one or more risk factors, which are measurable parameters that correlate with development of a particular disease, disorder, or condition, as known in the art. An individual having one or more of these risk factors has a higher probability of developing a particular disease, disorder, or condition than an individual without one or more of these risk factors.
- treatment refers to clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression, ameliorating or palliating the pathological state, and remission or improved prognosis of a particular disease, disorder, or condition.
- An individual is successfully “treated”, for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated.
- an “effective amount ” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
- An effective amount can be provided in one or more administrations.
- An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the treatment to elicit a desired response in the individual.
- An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
- beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
- beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
- An effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
- an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
- an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
- An “ individual ” for purposes of treatment, prevention, or reduction of risk refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, and the like. In some embodiments, the individual is human.
- administration “in conjunction ” with another compound or composition includes simultaneous administration and/or administration at different times.
- Administration in conjunction also encompasses administration as a co-formulation or administration as separate compositions, including at different dosing frequencies or intervals, and using the same route of administration or different routes of administration.
- administration in conjunction is administration as a part of the same treatment regimen.
- TMEM106B protein of the present disclosure includes, without limitation, a mammalian TMEM106B protein, human TMEM106B protein, primate TMEM106B protein, cynomolgus (cyno) TMEM106B protein, mouse TMEM106B protein, and rat TMEM106B protein. Additionally, anti-TMEM106B antibodies of the present disclosure may bind an epitope within one or more of a mammalian TMEM106B protein, human TMEM106B protein, primate TMEM106B, cyno TMEM106B protein, mouse TMEM106B protein, and rat TMEM106B protein.
- the present disclosure provides isolated (e.g., monoclonal) antibodies for use in treating, preventing, or reducing the risk of coronavirus infection, wherein the antibodies bind to an epitope within a TMEM106B protein of the present disclosure.
- TMEM106B proteins of the present disclosure include, without limitation, a mammalian TMEM106B protein, human TMEM106B protein, mouse TMEM106B protein, and cynomolgus TMEM106B protein.
- Human TMEM106B is a 274-amino acid protein that encodes a type 2 membrane glycoprotein.
- the amino acid sequence of human TMEM106B is set forth below (SEQ ID NO: 1): MGKSLSHLPLHSSKEDAYDGVTSENMR GLVN SEVHNEDGR GDVSQFPYVEFTGRDSVTCPT CQGTGRIPRGQENQLVALIPYSDQRLRPRRTKLYVMASVFVCLLLSGLAVFFLFPRSIDVKYIGVK S AYV SYD V QKRTIYFNITNTFNITN YY S VEVENITAQ V QF SKTVIGKARFN ITIIGPFDMKQID YTVPTVIAEEMSYMYDFCTFISIKVHNIVFMMQVTVTTTYFGHSEQISQERY QYVDCGRNTTY QF GQSEYFNVFQPQQQ
- TMEM106B protein is expressed in a cell. In some embodiments, TMEM106B protein is expressed in endosomes and/or lysosomes. In some embodiments, TMEM106B protein is expressed in late endosomes and/or late lysosomes. In some embodiments, TMEM106B protein is expressed on the cell surface.
- TMEM106B proteins of the present disclosure include several domains, including without limitation, an N-terminal luminal domain (predicted to range from amino acid residues 11-274 of human TMEM106B; see SEQ ID NO: 1), a transmembrane domain (predicted to range from amino acid residues 96-117 of human TMEM106B)), and a C-terminal domain (predicted to range from amino acid residues 1-92 of human TMEM106B).
- Epitope binning is a competitive immunoassay used to characterize and sort a library of monoclonal antibodies against a target protein (Abdiche et al, 2009, Analytical Biochemistry, 386: 172- 180). Epitope binning is also referred to as epitope mapping and epitope characterization (Brooks, 2014, Current Drug Discovery Technology, 11 : 109-112). Antibodies against a particular target (e.g ., TMEM106B) are tested against all other antibodies in the library in a pairwise fashion to determine if any of the antibodies block one another’s binding to an epitope of the target.
- TMEM106B e.g ., TMEM106B
- a competitive antibody blocking profile is created for each antibody relative to the other antibodies in the library.
- Closely related binning profiles indicate that the antibodies have the same or a closely related (e.g., overlapping) epitope and are “binned” together.
- anti-TMEM106B antibodies of the present disclosure displayed a variety of binning profiles, characterized by bin 1, bin 5, and bin 2 (bin 2 includes related sub bins 3 and 4).
- results provided herein show that anti-TMEM106B antibodies of the present disclosure that display overlapping or similar epitope binding characteristics (as evidenced by their binning profile) displayed varying degrees of effectiveness at reducing coronavirus cytopathic effect (CPE).
- anti-TMEM106B antibodies belonging to bin 2 were effective at reducing cell death (as measured by CPE assay) following coronavirus infection in vitro compared to that observed with anti-TMEM106B antibodies belonging to bins 1 or 5.
- Coronaviruses are a group of related enveloped positive-sense RNA viruses that cause disease in mammals and birds. Seven human coronaviruses (HCoVs) have been identified to date. These include four seasonally circulating human ‘common cold HCoVs’ and include the alphacoronaviruses 229E and NL63, and the betacoronaviruses OC43 and HKU1, each of which cause mild upper respiratory tract illnesses in humans. Three highly pathogenic coronaviruses emerged in the last two decades; these are the betacoronaviruses SARS-CoV, MERS-CoV, and the recently emerged SARS-CoV-2, each of which can cause severe, potentially lethal respiratory infections in humans. SARS-CoV-2 coronavirus is the virus responsible for Coronavirus Disease 2019 (COVID-19).
- the coronavirus RNA Upon receptor binding and membrane fusion to an infected cell, the coronavirus RNA is released into the cytoplasm, where it is translated to produce viral proteins.
- the viral replication/transcription complexes form on double-membrane vesicles within an infected cell and generate genome copies, which are then packaged into new virions via a budding process, through which they acquire the viral envelope, and the resulting virions are released from infected cells.
- Coronaviruses mainly target epithelial cells (e.g., epithelial cells of the respiratory tract), and require certain host factors in order to infect a cell. Such host factors may play a role in one or more steps of the coronavirus replication cycle (e.g., receptor binding, endocytosis, fusion, translation of viral replication proteins and structural proteins, genome replication, virion assembly, and virion release). Infected individuals are able to shed virus into the environment, which can lead to virus transmission to other individuals. In humans, SARS-CoV-2 coronavirus infects epithelial cells of the respiratory tract via an aerosol route by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.
- ACE2 angiotensin-converting enzyme 2
- TMEM106B has been identified as a host factor for SARS-CoV-2 coronavirus infection (Baggen et al, 2020, bioRxiv, doi:10.1101/2020.09.28.316281; Wang et al, 2020, bioRxiv, doi: 10.1101/2020/09.24.312298; Wang etal, 2021, Cell, 184:1-14). Genetic deletion of TMEM106B and genome-wide loss-of-function screens in human cells identified host factors important for infection and replication of SARS-CoV-2 coronavirus.
- CPE cytopathic effect
- SARS-CoV-2 coronavirus in cultured human cell lines derived from liver and lung.
- CPE refers to structural changes in a host cell resulting from viral infection. CPE occurs when the infecting virus causes lysis (dissolution) of the host cell or when the host cell dies without lysis because of its inability to reproduce. If a virus causes these morphological changes in the host cell, it is said to be cytopathogenic. Common examples of CPE include rounding of the infected cell, fusion with adjacent cells to form syncytia, and the appearance of nuclear or cytoplasmic inclusion bodies.
- provided herein are methods and compositions for treating, preventing, or reducing the risk of coronavirus infection.
- the methods and compositions provided herein are effective at treating, preventing, or reducing the risk of SARS-CoV-2 infection.
- the methods and compostions provided herein are effective at treating, preventing, or reducing the risk of SARS-CoV-2 infection, including variants of SARS-CoV-2 coronavirus, such as the alpha variant, the beta variant, the gamma variant, the delta variant, the lambda variant, etc.
- an anti-TMEM106B antibody of the present disclosure reduces coronavirus replication. In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM106B antibody of the present disclosure reduces coronavirus replication in vitro. In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM106B antibody of the present disclosure reduces coronavirus replication in vivo. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure reduces coronavirus infection. In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM106B antibody of the present disclosure reduces coronavirus infection in vitro. In some embodiments that may be combined with any of the embodiments provided herein, an anti-TMEM106B antibody of the present disclosure reduces coronavirus infection in vivo. In some embodiments that may be combined with any of the embodiments provided herein, the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure reduces the cytopathic effect (CPE) of coronavirus.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus infection by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus replication by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus transmission by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus assembly by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus release from an infected cell by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus entry into a cell by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- an anti-TMEM106B antibody of the present disclosure is effective at reducing coronavirus genome translation by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%.
- the coronavirus is SARS-CoV-2 coronavirus.
- anti-TMEM106B antibodies for use in treating, preventing, or reducing the risk of coronavirus infection, including anti-TMEM106B antibodies TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM- 17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM- 45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-
- amino acid sequences of exemplary anti-TMEM106B antibodies are provided below in Tables 1-6.
- an anti-TMEM106B antibody useful in the methods of the present disclosure comprises a heavy chain variable domain (V H ) amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence of the heavy chain variable domain (V H ) of an anti-TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM- 14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34,
- V H amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of the heavy chain variable domain (V H ) of an anti- TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM- 32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM
- TM-81, TM-82, TM-83, TM-84, TM-85, TM-86, TM-87, TM-88, TM- 89, TM90, TM-91, TM-92, TM-93, and TM-94 contains substitutions ( e.g ., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-TMEM106B antibody comprising that sequence retains the ability to bind to TMEM106B.
- a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain (VH) of an anti-TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM- 16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM- 44, TM-45, TM-46, TM-47, TM-
- a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the heavy chain variable domain (VH) of an anti-TMEM106B antibody selected form the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM- 27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48,
- VH
- substitutions, insertions, or deletions occur in regions outside the HVRs (i.e.. in the FRs).
- an anti-TMEM106B antibody of the present disclosure comprises the VH amino acid sequence of the heavy chain variable domain (VH) of an anti-TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM- 25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM
- the VH comprises an amino acid sequence provided in Table 5 and Table 6 below. In certain embodiments, the VH comprises one, two or three HVRs selected from the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences provided in Table 1 and Table 3 below.
- an anti-TMEM106B antibody useful in the methods of the present disclosure comprises a light chain variable domain (VL) amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the light chain variable domain (VL) of an anti-TMEM106B antibody selected from the group consisting of anti-TMEM106B antibody TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM- 23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34
- TM-81, TM-82, TM- 83, TM-84, TM-85, TM-86, TM-87, TM-88, TM-89, TM90, TM-91, TM-92, TM-93, and TM-94 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-TMEM106B antibody comprising that sequence retains the ability to bind to TMEM106B.
- a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the light chain variable domain (VL) of an anti-TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM- 11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM- 37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48
- a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the light chain variable domain (VL) of an anti-TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM- 34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48
- substitutions, insertions, or deletions occur in regions outside the HVRs (i.e.. in the FRs).
- an anti-TMEM106B antibody of the present disclosure comprises the V L sequence of the light chain variable domain (V L ) of an anti-TMEM106B antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM- 34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50
- the V L comprises an amino acid sequence provided in Table 5 and Table 6 below.
- the V L comprises one, two or three HVRs selected from the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences provided in Table 2 and Table 4 below.
- an anti-TMEM106B antibody is provided for use in the methods described herein, wherein the antibody comprises a V H as in any of the embodiments provided above, and a V L as in any of the embodiments provided above.
- provided herein are anti- TMEM106B antibodies, wherein the antibody comprises a V H as in any of the embodiments provided above, and a V L as in any of the embodiments provided above.
- the antibody comprises the V H and V L sequences of anti-TMEM106B antibody selected from the group consisting of anti-TMEM106B antibodies TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM- 11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM- 37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52
- an antibody competitively inhibits the binding to TMEM106B of an antibody comprising the heavy chain variable region and the light chain variable region of any one of the anti-TMEM106B antibodies selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM- 31, TM-32, TM-33, TM-34, TM-35, TM-37, TM-39, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-
- the antibody binds a truncated TMEM106B protein comprising amino acids 122-210 of SEQ ID NO: 1.
- the antibody is in Bin 2.
- the antibody is in Bin 3.
- the antibody is in Bin 4.
- the antibody is not in Bin 1.
- the antibody is not in Bin 5.
- Anti-TMEM106B antibodies for use in the methods of the present disclosure may bind to various regions of TMEM106B, including various regions of human TMEM106B. Such regions of TMEM106B include the cytoplasmic domain of TMEM106B or the luminal domain TMEM106B.
- an anti-TMEM106B antibody for use in the methods of the present disclosure binds to one or more regions or domains of TMEM106B. In some embodiments, an anti- TMEM106B antibody for use in the methods of the present disclosure binds to one or more regions or domains of human TMEM106B.
- an anti-TMEM106B antibody according to any of the above embodiments is a monoclonal antibody, including a humanized and/or human antibody.
- the anti-TMEM106B antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment.
- the anti-TMEM106B antibody is a substantially full-length antibody, e.g., an IgGl antibody, IgG2a antibody or other antibody class or isotype as defined herein.
- an anti-TMEM106B antibody useful in the any of the methods according to any of the above embodiments may incorporate any of the features, singly or in combination, as described in Sections 1-7 below:
- the antibody has a dissociation constant (Kd) of ⁇ 1 mM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 8 M or less, e.g., from 10 8 M to 10 13 M, e.g., from 10 9 M to 10 13 M).
- Kd dissociation constant
- Dissociation constants may be determined through any analytical technique, including any biochemical or biophysical technique such as ELISA, surface plasmon resonance (SPR), bio-layer interferometry (see, e.g., Octet System by ForteBio), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), circular dichroism (CD), stopped-flow analysis, and colorimetric or fluorescent protein melting analyses.
- Kd is measured by a radiolabeled antigen binding assay (RIA).
- RIA radiolabeled antigen binding assay
- an RIA is performed with the Fab version of an antibody of interest and its antigen, for example as described in Chen etal. J. Mol. Biol. 293:865-881(1999)).
- Kd is measured using a BIACORE surface plasmon resonance assay, for example, an assay using a BIACORE -2000 or a BIACORE -3000 (BIAcore, Inc., Piscataway, NJ) is performed at 25°C with immobilized antigen CM5 chips at ⁇ 10 response units (RU).
- the KD is determined using a monovalent antibody (e.g., a Fab) or a full-length antibody. In some embodiments, the KD is determined using a full- length antibody in a monovalent form.
- an anti-TMEM106B antibody of the present disclosure may have nanomolar or even picomolar affinities for TMEM106B.
- the dissociation constant (Kd) of the antibody is about 0. InM to about 500nM.
- the Kd of the antibody is any of about 500nM, about 400nM, about 300nM, about 200nM, about lOOnM, about 75 nM, about 50nM, about 25nM, about lOnM, about 9nM, about 8nM, about 7nM, about 6nM, about 5nM, about 4nM, about 3nM, about 2nM, about InM, or about InM to about 0. InM for binding to human TMEM106B.
- the antibody is an antibody fragment.
- Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, and other fragments described below.
- Fab fragment antigen
- Fab' fragment antigen binding domain
- Fab'-SH fragment antigen binding domain antigen binding domain antigen binding domain antigen binding domain antigen binding domain antigen binding domain antigen binding to antibodies.
- F(ab')2 Fv
- scFv fragments fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, and other fragments described below.
- scFv fragments see, e.g., WO 93/16185; and U.S. Patent Nos. 5571894 and 5587458.
- Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP404097; WO 1993/01161; Hudson etal. Nat. Med. 9: 129-134 (2003). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9: 129-134 (2003).
- Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
- a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No. 6248516).
- Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein. (3) Chimeric and Humanized antibodies
- the antibody is a chimeric antibody.
- Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4816567.
- a chimeric antibody comprises a non-human variable region (e.g. , a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
- a chimeric antibody is a "class switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
- the antibody is a humanized antibody.
- a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
- a humanized antibody is substantially non-immunogenic in humans.
- a humanized antibody has substantially the same affinity for a target as an antibody from another species from which the humanized antibody is derived. See, e.g., U.S. Pat. Nos. 5530101, 5693761; 5693762; and 5585089.
- amino acids of an antibody variable domain that can be modified without diminishing the native affinity of the antigen binding domain while reducing its immunogenicity are identified.
- a humanized antibody comprises one or more variable domains in which HVRs (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences.
- a humanized antibody optionally will also comprise at least a portion of a human constant region.
- some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), for example, to restore or improve antibody specificity or affinity.
- Humanized antibodies and methods of making them are reviewed, for example, in Almagro et al. Front. Biosci. 13:161 9-1633 (2008), and are further described, e.g., in US Patent Nos. 5821337, 7527791, 6982321, and 7087409.
- Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the "best- fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci.
- the antibody is a human antibody.
- Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk et ol. Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg Curr. Opin. Immunol. 20:450-459 (2008).
- Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
- Large human Ig fragments can preserve the large variable gene diversity as well as the proper regulation of antibody production and expression.
- the reproduced human antibody repertoire in these mouse strains can yield high affinity fully human antibodies against any antigen of interest, including human antigens.
- antigen-specific human monoclonal antibodies with the desired specificity can be produced and selected.
- Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. 133:3001 (1984) and Boemer etal. J. Immunol. 147:86 (1991)). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al. Proc. Natl. Acad. Sci. USA, 1 03:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7189826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines).
- Human hybridoma technology (Trioma technology) is also described in Vollmers et al. Histology and Histopathology 20(3) :927-937 (2005) and Vollmers et al. Methods and Findings in Experimental and Clinical Pharmacology 27(3): 185-91 (2005).
- Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
- the antibody is a human antibody isolated by in vitro methods and/or screening combinatorial libraries for antibodies with the desired activity or activities. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display (Adimab), and the like.
- repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al. Ann. Rev. Immunol. 12: 433-455 (1994).
- PCR polymerase chain reaction
- a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. See also Sidhu et al. J. Mol. Biol. 338(2): 299-310, 2004; Lee et al. J. Mol. Biol. 340(5): 1073-1093, 2004; Fellouse Proc. Natl. Acad. Sci.
- Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments.
- Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
- the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al. EMBOJ. 12: 725-734 (1993).
- naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers comprising random sequence to encode the highly variable HVR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom et al. J. Mol. Biol., 227: 381-388, 1992.
- Patent publications describing human antibody phage libraries include, for example: US Patent No. 5750373, and US Patent Publication Nos. 2007/0292936 and 2009/0002360.
- Antibodies isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
- the antibody comprises an Fc.
- the Fc is a human IgGl, IgG2, IgG3, and/or IgG4 isotype.
- the antibody is of the IgG class, the IgM class, or the IgA class.
- the antibody has an IgG2 isotype.
- the antibody contains a human IgG2 constant region.
- the human IgG2 constant region includes an Fc region.
- the antibody induces the one or more TMEM106B activities or independently of binding to an Fc receptor.
- the antibody binds an inhibitory Fc receptor.
- the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcyllB).
- the antibody has an IgGl isotype. In some embodiments, the antibody contains a mouse IgGl constant region. In some embodiments, the antibody contains a human IgGl constant region. In some embodiments, the human IgGl constant region includes an Fc region. In some embodiments, the antibody binds an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcyllB). [0132] In certain embodiments of any of the antibodies provided herein, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region.
- the human IgG4 constant region includes an Fc region.
- the antibody binds an inhibitory Fc receptor.
- the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcyllB).
- the antibody has a hybrid IgG2/4 isotype.
- the antibody includes an amino acid sequence comprising amino acids 118 to 260 according to EU numbering of human IgG2 and amino acids 261-447 according to EU numbering of human IgG4 (WO 1997/11971; WO 2007/106585).
- the Fc region increases clustering without activating complement as compared to a corresponding antibody comprising an Fc region that does not comprise the amino acid substitutions.
- the antibody induces one or more activities of a target specifically bound by the antibody.
- the antibody binds to TMEM106B.
- an anti-TMEM106B antibody of the present disclosure may also be desirable to modify effector function and/or to increase serum half-life of the antibody.
- the Fc receptor binding site on the constant region may be modified or mutated to remove or reduce binding affinity to certain Fc receptors, such as FcyRI, FcyRII, and/or FcyRIII to reduce Antibody-dependent cell-mediated cytotoxicity.
- the effector function is impaired by removing N-glycosylation of the Fc region (e.g., in the CH2 domain of IgG) of the antibody.
- the effector function is impaired by modifying regions such as 233-236, 297, and/or 327-331 of human IgG as described in WO 99/58572 and Armour et al. Molecular Immunology 40: 585-593 (2003); Reddy et al. J. Immunology 164: 1925-1933 (2000).
- salvage receptor binding epitope refers to an epitope of the Fc region of an IgG molecule (e.g., IgGi, IgG2, IgG 3 , or IgG-i) that is responsible for increasing the in vivo serum half-life of the IgG molecule.
- IgGi an epitope of the Fc region of an IgG molecule
- IgG-i an epitope of the Fc region of an IgG molecule
- Multispecific antibodies are antibodies that have binding specificities for at least two different epitopes, including those on the same or another polypeptide (e.g., one or more TMEM106B polypeptides of the present disclosure).
- the multispecific antibody can be a bispecific antibody.
- the multispecific antibody can be a trispecific antibody.
- the multispecific antibody can be a tetraspecific antibody.
- Such antibodies can be derived from full-length antibodies or antibody fragments (e.g., F(ab’)2bispecific antibodies).
- the multispecific antibody comprises a first antigen binding region which binds to first site on TMEM106B and comprises a second antigen binding region which binds to a second site on TMEM106B. In some embodiment, the multispecific antibodies comprises a first antigen binding region which binds to TMEM106B and a second antigen binding region that binds to a second polypeptide.
- multispecific antibodies comprises a first antigen binding region, wherein the first antigen binding region comprises the six HVRs of an antibody described herein, which binds to TMEM106B and a second antigen binding region that binds to a second polypeptide.
- the first antigen binding region comprises the V H or V L of an antibody described herein.
- the multivalent antibodies may recognize the TMEM106B antigen as well as without limitation additional antigens, such as a coronavirus viral entry factor, including angiotensin-converting enzyme 2 (ACE2), which is a viral entry receptor for HCoV-NL63, SARS-CoV-1, and SARS-CoV-2.
- ACE2 angiotensin-converting enzyme 2
- the multivalent antibody contains at least one polypeptide chain (and preferably two polypeptide chains), wherein the polypeptide chain or chains comprise two or more variable domains.
- the polypeptide chain or chains may comprise VDl-(Xl) n -VD2-(X2) n -Fc, wherein VD1 is a first variable domain, VD2 is a second variable domain, Fc is one polypeptide chain of an Fc region, XI and X2 represent an amino acid or polypeptide, and n is 0 or 1.
- the polypeptide chain or chains may comprise V H -C H 1 -flexible linker-V H -C H l-Fc region chain; or V H -C H 1-V H -C H 1-FC region chain.
- the multivalent antibody herein preferably further comprises at least two (and preferably four) light chain variable domain polypeptides.
- the multivalent antibody herein may, for instance, comprise from about two to about eight light chain variable domain polypeptides.
- the light chain variable domain polypeptides contemplated here comprise a light chain variable domain and, optionally, further comprise a CF domain.
- Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain- light chain pairs having different specificities (see Milstein and Cuello Nature 305: 537 (1983), WO 93/08829, and Traunecker et al. EMBO J. 10:3655 (1991)), and "knob-in-hole” engineering (see, e.g., U.S. Patent No. 5731168). See also WO 2013/026833 (CrossMab).
- Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc- heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies (see, e.g., US Patent No. 4676980); using leucine; using "diabody” technology for making bispecific antibody fragments (see, e.g., Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); and using single-chain Fv (scFv) dimers (see, e.g., Gruber et al. J. Immunol. 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991).
- Engineered antibodies with three or more functional antigen binding sites are also included herein (see, e.g., US 2006/0025576).
- the antibody herein also includes a "Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to multiple TMEM106B (see, US 2008/0069820, for example).
- amino acid sequence variants of the antibodies are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody.
- antibody variants having one or more amino acid substitutions are provided.
- Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody.
- Substantial modifications in the biological properties of the antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
- Naturally occurring residues are divided into groups based on common side-chain properties:
- non-conservative substitutions can involve the exchange of a member of one of these classes for a member from another class.
- Such substituted residues can be introduced, for example, into regions of a human antibody that are homologous with non-human antibodies, or into the non- homologous regions of the molecule.
- the hydropathic index of amino acids can be considered.
- Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
- the substitution of like amino acids can be made effectively on the basis of hydrophilicity, particularly where the biologically functional protein or peptide thereby created is intended for use in immunological embodiments, as in the present case.
- the greatest local average hydrophilicity of a protein as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e., with a biological property of the protein.
- hydrophilicity values have been assigned to these amino acid residues: arginine ( ⁇ 3.0); lysine ( ⁇ 3.0 ⁇ 1); aspartate ( ⁇ 3.0 ⁇ 1); glutamate ( ⁇ 3.0 ⁇ 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ⁇ 1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4).
- the substitution of amino acids whose hydrophilicity values are within ⁇ 2 is included, in certain embodiments, those which are within ⁇ 1 are included, and in certain embodiments, those within ⁇ 0.5 are included.
- substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
- conservative alterations e.g ., conservative substitutions as provided herein
- Such alterations may, for example, be outside of antigen contacting residues in the HVRs.
- each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.
- Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides comprising a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
- terminal insertions include an antibody with an N-terminal methionyl residue.
- Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. , for ADEPT) or a polypeptide which increases the serum half-life of the antibody.
- cysteine residues not involved in maintaining the proper conformation of the antibody also may be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking.
- cysteine bond(s) may be added to the antibody to improve its stability (particularly where the antibody is an antibody fragment, such as an Fv fragment).
- the antibody is altered to increase or decrease the extent to which the antibody is glycosylated.
- Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
- N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
- the tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
- X is any amino acid except proline
- O-linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5- hydroxy lysine may also be used.
- Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N- linked glycosylation sites).
- the alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).
- the carbohydrate attached thereto may be altered.
- Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 according to Kabat numbering of the CH2 domain of the Fc region.
- the oligosaccharide may include various carbohydrates, for example, mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the "stem" of the biantennary oligosaccharide structure.
- modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.
- antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. See, e.g.. US Patent Publication Nos.
- knockout cell lines such as alpha- 1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see. e.g., Yamane-Ohnuki etal. Biotech. Bioeng. 87: 614 (2004) and Kanda et al. Biotechnol. Bioeng. 94(4):680- 688 (2006)).
- the antibody Fc is an antibody Fc isotypes and/or modifications. In some embodiments, the antibody Fc isotype and/or modification is capable of binding to Fc gamma receptor.
- the modified antibody Fc is an IgGl modified Fc.
- the IgGl modified Fc comprises one or more modifications.
- the IgGl modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype).
- the one or more amino acid substitutions are selected fromN297A (Bolt S et al. (1993) Eur J Immunol 23:403- 411), D265A (Shields etal. (2001) R. J. Biol. Chem.
- the Fc comprises N297A mutation according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises D265A and N297A mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises D270A mutations according to EU numbering. In some embodiments, the IgGl modified Fc comprises L234A and L235A mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises L234A and G237A mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises L234A,
- the Fc comprises one or more (including all) of P238D, L328E, E233, G237D, H268D, P271G and A33 OR mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises one or more of S267E/L328F mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises P238D, L328E, E233D, G237D, H268D, P271G and A330R mutations according to EU numbering.
- the Fc comprises P238D, L328E, G237D, H268D, P271G and A33 OR mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises P238D, S267E, L328E, E233D, G237D, H268D, P271G and A33 OR mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises P238D, S267E, L328E, G237D, H268D, P271G and A33 OR mutations according to EU numbering.
- the Fc comprises C226S, C229S, E233P, L234V, and L235A mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises F234F, F235E, and P33 IS mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises S267E and F328F mutations according to EU numbering. In some embodiments of any of the IgGl modified Fc, the Fc comprises S267E mutations according to EU numbering.
- the Fc comprises a substitute of the constant heavy 1 (CHI) and hinge region of IgGl with CHI and hinge region of IgG2 (amino acids 118- 230 of IgG2 according to EU numbering) with a Kappa light chain.
- CHI constant heavy 1
- IgG2 amino acids 118- 230 of IgG2 according to EU numbering
- the Fc includes two or more amino acid substitutions that increase antibody clustering without activating complement as compared to a corresponding antibody having an Fc region that does not include the two or more amino acid substitutions.
- the IgGl modified Fc is an antibody comprising an Fc region, where the antibody comprises an amino acid substitution at position E430G and one or more amino acid substitutions in the Fc region at a residue position selected from: F234F, F235A, F235E, S267E, K322A, F328F, A330S, P331S, and any combination thereof according to EU numbering.
- the IgGl modified Fc comprises an amino acid substitution at positions E430G, F243A, F235A, and P33 IS according to EU numbering. In some embodiments, the IgGl modified Fc comprises an amino acid substitution at positions E430G and P33 IS according to EU numbering. In some embodiments, the IgGl modified Fc comprises an amino acid substitution at positions E430G and K322A according to EU numbering. In some embodiments, the IgGl modified Fc comprises an amino acid substitution at positions E430G, A330S, and P331S according to EU numbering. In some embodiments, the IgGl modified Fc comprises an amino acid substitution at positions E430G, K322A, A330S, and P331S according to EU numbering.
- the IgGl modified Fc comprises an amino acid substitution at positions E430G, K322A, and A330S according to EU numbering. In some embodiments, the IgGl modified Fc comprises an amino acid substitution at positions E430G, K322A, and P331S according to EU numbering.
- the IgGl modified Fc may further comprise herein may be combined with an A330F mutation (Fazar el al. Proc Natl Acad Sci USA, 103:4005-4010 (2006)), or one or more ofF234F, F235E, and/or P33 IS mutations (Sazinsky et al. Proc Natl Acad Sci USA, 105:20167-20172 (2008)), according to the EU numbering convention, to eliminate complement activation.
- A330F mutation Fazar el al. Proc Natl Acad Sci USA, 103:4005-4010 (2006)
- F234F, F235E, and/or P33 IS mutations Sazinsky et al. Proc Natl Acad Sci USA, 105:20167-20172 (2008)
- the IgGl modified Fc may further comprise one or more of A330F, A330S, F234F, F235E, and/or P33 IS according to EU numbering.
- the IgGl modified Fc may further comprise one or more mutations to enhance the antibody half-life in human serum (e.g., one or more (including all) of M252Y, S254T, and T256E mutations according to the EU numbering convention).
- the IgGl modified Fc may further comprise one or more of E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, and/or S440W according to EU numbering.
- Fc regions modified constant regions
- An antibody dependent on binding to FcgR receptor to activate targeted receptors may lose its agonist activity if engineered to eliminate FcgR binding (see, e.g., Wilson el al. Cancer Cell 19:101-113 (2011); Armour at al. Immunology 40:585-593 (2003); and White et al. Cancer Cell 27 : 138- 148 (2015)).
- an anti-TMEM106B antibody of the present disclosure with the correct epitope specificity can activate the target antigen, with minimal adverse effects, when the antibody has an Fc domain from a human IgG2 isotype (CHI and hinge region) or another type of Fc domain that is capable of preferentially binding the inhibitory FcgRIIB r receptors, or a variation thereof.
- the modified antibody Fc is an IgG2 modified Fc.
- the IgG2 modified Fc comprises one or more modifications.
- the IgG2 modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype).
- the one or more amino acid substitutions are selected from V234A (Alegre et al. Transplantation 57:1537-1543 (1994); Xu et al. Cell Immunol, 200:16-26 (2000)); G237A (Cole et al.
- the Fc comprises an amino acid substitution at positions V234A and G237A according to EU numbering. In some embodiments of any of the IgG2 modified Fc, the Fc comprises an amino acid substitution at positions C219S or C220S according to EU numbering. In some embodiments of any of the IgG2 modified Fc, the Fc comprises an amino acid substitution at positions A330S and P33 IS according to EU numbering. In some embodiments of any of the IgG2 modified Fc, the Fc comprises an amino acid substitution at positions S267E and F328F according to EU numbering.
- the Fc comprises a C127S amino acid substitution according to the EU numbering convention (White etal., (2015) Cancer Cell 27, 138-148; Fightle et al. Protein Sci. 19:753-762 (2010); and WO 2008/079246).
- the antibody has an IgG2 isotype with a Kappa light chain constant domain that comprises a C214S amino acid substitution according to the EU numbering convention (White etal. Cancer Cell 27: 138-148 (2015); Fightle etal. Protein Sci. 19:753-762 (2010); and WO 2008/079246).
- the Fc comprises a C220S amino acid substitution according to the EU numbering convention.
- the antibody has an IgG2 isotype with a Kappa light chain constant domain that comprises a C214S amino acid substitution according to the EU numbering convention.
- the Fc comprises a C219S amino acid substitution according to the EU numbering convention.
- the antibody has an IgG2 isotype with a Kappa light chain constant domain that comprises a C214S amino acid substitution according to the EU numbering convention.
- the Fc includes an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region (White el al. Cancer Cell 27: 138-148 (2015)).
- the IgG2 isotype CHI and hinge region comprise the amino acid sequence of 118-230 according to EU numbering.
- the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and/or a N297A or N297Q amino acid substitution according to the EU numbering convention.
- the Fc further comprises one or more amino acid substitution at positions E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, and S440W according to EU numbering.
- the Fc may further comprise one or more mutations to enhance the antibody half-life in human serum (e.g ., one or more (including all) of M252Y, S254T, and T256E mutations according to the EU numbering convention).
- the Fc may further comprise A330S and P331S.
- the Fc is an IgG2/4 hybrid Fc.
- the IgG2/4 hybrid Fc comprises IgG2 aa 118 to 260 and IgG4 aa 261 to 447.
- the Fc comprises one or more amino acid substitutions at positions H268Q, V309L, A330S, and P331S according to EU numbering.
- the Fc comprises one or more additional amino acid substitutions selected from A330L, L234F; L235E, or P331S according to EU numbering; and any combination thereof.
- the Fc comprises one or more amino acid substitutions at a residue position selected from C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P33 IS, E345R, E430G, S440Y, and any combination thereof according to EU numbering.
- the Fc comprises an amino acid substitution at positions E430G, L243A, L235A, and P33 IS according to EU numbering.
- the Fc comprises an amino acid substitution at positions E430G and P33 IS according to EU numbering. In some embodiments of any of the IgGl and/or IgG2 modified Fc, the Fc comprises an amino acid substitution at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgGl and/or IgG2 modified Fc, the Fc comprises an amino acid substitution at positions E430G, A330S, and P33 IS according to EU numbering.
- the Fc comprises an amino acid substitution at positions E430G, K322A, A330S, and P33 IS according to EU numbering. In some embodiments of any of the IgGl and/or IgG2 modified Fc, the Fc comprises an amino acid substitution at positions E430G, K322A, and A330S according to EU numbering. In some embodiments of any of the IgGl and/or IgG2 modified Fc, the Fc comprises an amino acid substitution at positions E430G, K322A, and P331S according to EU numbering.
- the Fc comprises an amino acid substitution at positions S267E and F328F according to EU numbering. In some embodiments of any of the IgGl and/or IgG2 modified Fc, the Fc comprises an amino acid substitution at position C127S according to EU numbering. In some embodiments of any of the IgGl and/or IgG2 modified Fc, the Fc comprises an amino acid substitution at positions E345R, E430G and S440Y according to EU numbering.
- the modified antibody Fc is an IgG4 modified Fc.
- the IgG4 modified Fc comprises one or more modifications.
- the IgG4 modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype).
- the one or more amino acid substitutions are selected from F235A, G237A, S229P, F236E (Reddy etal.
- the Fc may further comprise F235A, G237A, and E318A according to the EU numbering convention. In some embodiments of any of the IgG4 modified Fc, the Fc may further comprise S228P and F235E according to the EU numbering convention. In some embodiments of any of the IgG4 modified Fc, the IgG4 modified Fc may further comprise S267E and F328F according to the EU numbering convention.
- the IgG4 modified Fc comprises may be combined with an S228P mutation according to the EU numbering convention (Angal et al. Mol Immunol. 30: 105-108 (1993)) and/or with one or more mutations described in (Peters et al. J Biol Chem. 287(29):24525-33 (2012)) to enhance antibody stabilization.
- the IgG4 modified Fc may further comprise one or more mutations to enhance the antibody half-life in human serum (e.g., one or more (including all) of M252Y, S254T, and T256E mutations according to the EU numbering convention).
- the Fc comprises F235E according to EU numbering.
- the Fc comprises one or more amino acid substitutions at a residue position selected from C127S, F234A, L235A, L235E, S267E, K322A, L328F, E345R, E430G, S440Y, and any combination thereof, according to EU numbering.
- the Fc comprises an amino acid substitution at positions E430G, L243A, L235A, and P33 IS according to EU numbering.
- the Fc comprises an amino acid substitution at positions E430G and P33 IS according to EU numbering.
- the Fc comprises an amino acid substitution at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgG4 modified Fc, the Fc comprises an amino acid substitution at position E430 according to EU numbering. In some embodiments of any of the IgG4 modified Fc, the Fc region comprises an amino acid substitution at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgG4 modified Fc, the Fc comprises an amino acid substitution at positions S267E and L328F according to EU numbering. In some embodiments of any of the IgG4 modified Fc, the Fc comprises an amino acid substitution at position C127S according to EU numbering. In some embodiments of any of the IgG4 modified Fc, the Fc comprises an amino acid substitution at positions E345R, E430G and S440Y according to EU numbering.
- the antibody is a derivative.
- derivative refers to a molecule that includes a chemical modification other than an insertion, deletion, or substitution of amino acids (or nucleic acids).
- derivatives comprise covalent modifications, including, but not limited to, chemical bonding with polymers, lipids, or other organic or inorganic moieties.
- a chemically modified antigen binding protein can have a greater circulating half-life than an antigen binding protein that is not chemically modified.
- a chemically modified antigen binding protein can have improved targeting capacity for desired cells, tissues, and/or organs.
- a derivative antigen binding protein is covalently modified to include one or more water soluble polymer attachments, including, but not limited to, polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. See, e.g.. U.S. Pat. Nos. 4640835, 4496689, 4301144, 4670417, 4791192 and 4179337.
- a derivative antigen binding protein comprises one or more polymer, including, but not limited to, monomethoxy- polyethylene glycol, dextran, cellulose, , copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers.
- polymer including, but not limited to, monomethoxy- polyethylene glycol, dextran, cellulose, , copolymers of ethylene glyco
- a derivative is covalently modified with polyethylene glycol (PEG) subunits.
- PEG polyethylene glycol
- one or more water-soluble polymer is bonded at one or more specific position, for example at the amino terminus, of a derivative.
- one or more water- soluble polymer is randomly attached to one or more side chains of a derivative.
- PEG is used to improve the therapeutic capacity for an antigen binding protein.
- PEG is used to improve the therapeutic capacity for a humanized antibody.
- Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed “peptide mimetics” or “peptidomimetics.” Fauchere, J. Adv. Drug Res., 15:29 (1986); and Evans etal. J. Med. Chem., 30: 1229 (1987), which are incorporated herein by reference for any purpose. Such compounds are often developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides can be used to produce a similar therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e.. a polypeptide that has a biochemical property or pharmacological activity), such as human antibody, but have one or more peptide linkages optionally replaced by a linkage selected from: -CEENH-, -CEES-, -
- a paradigm polypeptide
- Drug conjugation involves coupling of a biological active cytotoxic (anticancer) payload or drug to an antibody that specifically targets a certain tumor marker (e.g. a polypeptide that, ideally, is only to be found in or on tumor cells).
- a certain tumor marker e.g. a polypeptide that, ideally, is only to be found in or on tumor cells.
- Antibodies track these proteins down in the body and attach themselves to the surface of cancer cells.
- the biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the tumor cell, which then absorbs or internalizes the antibody together with the cytotoxin.
- the cytotoxic drug is released and kills the cancer. Due to this targeting, ideally the dmg has lower side effects and gives a wider therapeutic window than other chemotherapeutic agents.
- Anti-TMEM106B antibodies of the present disclosure may be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4816567.
- isolated nucleic acids having a nucleotide sequence encoding any of the anti-TMEM106B antibodies of the present disclosure are provided.
- Such nucleic acids may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the anti-TMEM106B antibody (e.g. , the light and/or heavy chains of the antibody).
- one or more vectors comprising such nucleic acids are provided.
- a host cell comprising such nucleic acid is also provided.
- the host cell comprises (e.g., has been transduced with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody.
- the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NSO, Sp20 cell).
- Host cells of the present disclosure also include, without limitation, isolated cells, in vitro cultured cells, and ex vivo cultured cells.
- Methods of making an anti-TMEM106B antibody of the present disclosure include culturing a host cell of the present disclosure comprising a nucleic acid encoding the anti-TMEM106B antibody, under conditions suitable for expression of the antibody. In some embodiments, the antibody is subsequently recovered from the host cell (or host cell culture medium).
- nucleic acid encoding the anti-TMEM106B antibody is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
- nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
- Suitable vectors comprising a nucleic acid sequence encoding any of the anti-TMEM106B antibodies of the present disclosure, or cell-surface expressed fragments or polypeptides thereof polypeptides (including antibodies) described herein include, without limitation, cloning vectors and expression vectors. Suitable cloning vectors can be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art.
- cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones comprising the vector. Suitable examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mpl8, mpl9, pBR322, pMB9, ColEl, pCRl, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial vendors such as BioRad, Strategene, and Invitrogen.
- Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells.
- anti-TMEM106B antibodies of the present disclosure may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
- antibody fragments and polypeptides in bacteria e.g., U.S. Patent Nos. 5648237, 5789199, and 5840523. After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.
- eukaryotic microorganisms such as filamentous fungi or yeast
- suitable cloning or expression hosts for antibody-encoding vectors including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern (e.g., Gemgross Nat. Biotech. 22: 1409-1414 (2004); and Fi etal. Nat. Biotech. 24:210-215 (2006)).
- Suitable host cells for the expression of glycosylated antibody can also be derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells. Plant cell cultures can also be utilized as hosts (e.g., U.S. Patent Nos. 5959177, 6040498, 6420548, 7125978, and 6417429, describing PFANTIBODIESTM technology for producing antibodies in transgenic plants).
- Vertebrate cells may also be used as hosts.
- mammalian cell lines that are adapted to grow in suspension may be useful.
- useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham etal. J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod.
- monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HEFA); canine kidney cells (MDCK; buffalo rat liver cells (BRF 3 A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather el al. Annals NY. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells.
- Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al. Proc. Natl. Acad. Sci.
- compositions and/or pharmaceutical formulations comprising the anti-TMEM106B antibodies of the present disclosure and a pharmaceutically acceptable carrier for use, e.g., in treating, preventing, or reducing the risk of coronavirus infection.
- the antibody or antigen-binding fragment thereof having the desired degree of purity is present in a formulation comprising, e.g., a physiologically acceptable carrier, excipient or stabilizer (Remington’s Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA).
- pharmaceutically acceptable carriers preferably are nontoxic to recipients at the dosages and concentrations employed.
- Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can comprise antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
- a pharmaceutical composition comprises an anti-TMEM106B antibody or antigen-binding fragment thereof as described herein, and a pharmaceutically acceptable carrier (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Fippencott Williams and Wilkins (2004); Kibbe et ah, Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)).
- Pharmaceutical compositions described herein are, in some aspects, for use as a medicament.
- the compositions to be used for in vivo administration can be sterile. This is readily accomplished by fdtration through, e.g., sterile fdtration membranes.
- a pharmaceutical composition described herein can be used to exert a biological effect(s), e.g., treating, preventing, or reducing the risk of coronavirus infection, in vivo.
- the present disclosure provides methods for treating, preventing, or reducing risk of coronavirus infection by administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to TMEM106B protein.
- the coronavirus infection is SARS-CoV-2 coronavirus infection and the methods provided herein are effective at treating, preventing, or reducing the risk of SARS-CoV-2 coronavirus infection.
- the present disclosure provides methods for preventing or reducing coronavirus transmission, wherein the method comprises administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to TMEM106B protein, thereby preventing or reducing coronavirus transmission.
- the coronavirus is SARS-CoV-2 coronavirus and the methods provided herein are effective at preventing or reducing SARS-CoV-2 coronavirus transmission.
- Anti-TMEM106B antibodies of the present disclosure are effective at treating coronavirus infection over a range of clinical manifestations of coronavirus infection, including asymptomatic or pre symptomatic infection, mild illness, moderate illness, severe illness, and critical illness.
- a subject or individual is a mammal.
- Mammals include, without limitation, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
- the subject or individual is a human.
- An antibody provided herein can be administered by any suitable means, including parenteral, intrapulmonary, intranasal, intralesional administration, intracerobrospinal, intracranial, intraspinal, intrasynovial, intrathecal, oral, topical, or inhalation routes.
- Parenteral infusions include intramuscular, intravenous administration as a bolus or by continuous infusion over a period of time, intraarterial, intra-articular, intraperitoneal, or subcutaneous administration.
- the administration is intravenous administration.
- the administration is subcutaneous. Dosing can be by any suitable route, e.g.
- injections such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
- Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.
- Antibodies provided herein would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
- the antibody need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically/clinically determined to be appropriate.
- an anti-TMEM106B antibody for treating, preventing, or reducing risk of coronavirus infection in combination with other therapies, including, for example, dexamethasone, remdesivir, baricitinib, casirivimab, imdevimab, bamlanivimab, or any combination thereof.
- an antibody of the present disclosure reduces a cytopathic effect in a cell infected with SARS-CoV-2, optionally wherein the cell is a VeroE6 cell or a NCI-H1975 cell.
- an antibody of the invention when used alone or in combination with one or more other additional therapeutic agents, will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
- the antibody is suitably administered to the patient at one time or over a series of treatments.
- Article of manufacture may include one or more containers comprising an antibody described herein.
- Containers may be any suitable packaging including, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
- the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
- kits may further include a second agent.
- the second agent is a pharmaceutically-acceptable buffer or diluting agent including, but not limited to, such as bacteriostatic water for injection (BWFI), phosphate- buffered saline, Ringer's solution and dextrose solution.
- BWFI bacteriostatic water for injection
- phosphate- buffered saline Ringer's solution
- dextrose solution a pharmaceutically active agent.
- the article of manufactures further include instructions for use in accordance with the methods of this disclosure.
- the instructions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
- these instructions comprise a description of administration of the isolated antibody of the present disclosure (e.g., an anti-TMEM106B antibody described herein) to prevent, reduce risk, or treat an individual having a disease, disorder, or injury selected from frontotemporal lobar degeneration, frontotemporal dementia, frontotemporal dementia with progranulin mutations, frontotemporal dementia with C9orf72 mutations, frontotemporal lobar degeneration with TDP-43 inclusions, TDP-43 proteinopathy, hippocampal sclerosis (HpScl), hippocampal sclerosis of aging (HS-Aging), cognitive impairments associated with various disorders (including without limitation cognitive impairment in amyotrophic lateral sclerosis), and hypomyelinating disorder (including without limitation hypomyelinating
- mice (JAX 100008, Jackson Laboratory, Bar Harbor, ME), SJL mice (JAX000686, Jackson Laboratory), or TMEM106B .knockout mice (Taconic, Rensselaer, NY) were co immunized weekly with 50pg each of plasmid DNA encoding full-length human, cynomolgus (cyno), or mouse TMEM106B with or without mFlt3 ligand (DNA) and mGM-CSF (DNA) (Invitrogen, San Diego, CA) diluted in lactated Ringer's solution. A total of 5-7 injections of the TMEM106B expression plasmids for DNA immunizations were performed per mouse.
- Spleens were harvested from the mice three days following the final DNA immunization. Sera from the mice were analyzed for reactivity to TMEM106B by FACS analyses using HEK293 cells overexpressing human, cyno, and/or mouse TMEM106B.
- Splenocytes from mice whose sera demonstrated strong binding to HEK293 cells overexpressing human, cyno, and/or mouse TMEM106B were fused with P3X63Ag8.653 mouse myeloma cells (CRL-1580, American Type Culture Collection, Rockville, MD) via electrofusion (ECM 2001, BTX, Holliston, MA) and incubated at 37°C/5% C02 overnight in Clonacell-HY Medium C (StemCell Technologies, Vancouver, BC, Canada).
- Fusion A using splenocytes obtained from immunized TMEM106B .knockout mice
- Fusion B using splenocytes obtained from immunized SJL mice
- Fusion C using splenocytes obtained from immunized NZB/W mice.
- TMEM106B over-expressing cells were produced via transient transfection of HEK293 cells using the lipofectamine system. To ensure reproducibility across screening experiments, a large bank of transfected cells ( ⁇ lxl0 9 ) was prepared in a single round of transient transfection, and aliquoted and frozen for all further screening experiments. [0212] For screening of the hybridoma cell culture supernatants, humanTMEM106B-transfected HEK293 cells were aliquoted in 96-well round bottom plates (2xl0 5 cells per well) and incubated with 50 pL of hybridoma cell culture supernatant on ice for 30 minutes.
- the cells were washed twice with 175 pL of ice-cold FACS buffer (PBS + 1% FBS + 2mM EDTA), and then further incubated on ice for 20 minutes with anti-mouse IgG Fc-APC (Jackson Labs, Cat# 115-136-071) (diluted 1:500). Following this secondary incubation, the cells were again washed twice with ice-cold FACS buffer and resuspended in a final volume of 30 pL of FACS buffer + 0.25pl/well propidium iodide (BD Biosciences Cat#556463).
- ice-cold FACS buffer PBS + 1% FBS + 2mM EDTA
- anti-mouse IgG Fc-APC Jackson Labs, Cat# 115-136-071
- MFI Median fluorescence intensity
- EXAMPLE 2 Antibody heavy chain and light chain variable domain sequences
- Amino acid sequences were determined for anti-TMEM106B antibodies identified as described above. Using standard techniques, the amino acid sequences encoding the light chain variable regions and the heavy chain variable regions of the generated antibodies were determined.
- the Kabat heavy chain CDR (HVR) amino acid sequences and the Kabat light chain CDR (HVR) amino sequences of the antibodies are set forth below in Table 1, Table 2, Table 3, and Table 4.
- the amino acid sequences for the heavy chain and light chain variable regions of the anti-TMEM106B antibodies are set forth below in Table 5 and Table 6. In both Table 5 and Table 6, the CDR (HVR) regions, as defined by Kabat, are underlined.
- TMEM106B has been identified as a host factor for SARS-CoV-2 coronavirus infection.
- the anti-viral activity of anti-TMEM106B antibodies toward SARS-CoV-2 coronavirus infectivity and/or replication is determined by various in vitro and in vivo methodologies known and available to one of skill in the art for assessing anti-viral activity of an antibody.
- VeroE6 cells African green monkey kidney epithelial cells
- SARS-CoV-2 virus such as, for example, SARS-CoV-2 coronavirus Washington 2019 virus strain
- MOI multiplicity of infection
- cells are fixated and stained with neutral red. Cytotoxicity is evaluated using standard methods. Cell viability is measured using methods known to one of skill in the art, such as, for example, fixation and staining of surviving cells with crystal violet.
- Viral cytopathic effect is also determined.
- Intracellular SARS-CoV-2 virus levels in non-fixated cells are determined using RT-qPCR quantification, which further provides a measurement of the effect of anti-TMEM106B antibodies on SARS-CoV-2 viral replication.
- cell lines derived from human liver e.g ., Huh7 cells, Hep3B cells
- cell lines derived from human lung e.g ., A549 cells, NCI-H1975 cells, NCI-H2110 cells.
- Results from these in vitro experiments provide an assessment of the anti-viral effect of anti- TMEM106B antibodies on SARS-CoV-2 virus infection and/or SARS-CoV-2 virus replication, including the effect of anti-TMEM106B antibodies on SAR-CoV-2-induced cytopathic effect (CPE).
- CPE SAR-CoV-2-induced cytopathic effect
- VeroE6 cells were incubated with anti-TMEM106B antibodies of the present disclosure ( ⁇ 1 OOpg/ml) for 1 hour. The cells were then incubated with a dilution series of SARS-CoV-2 coronavirus (Washington 2019 virus strain) as described above. Viral cytopathic effect (CPE), as measured by cell viability/survival, was assessed as described above. The results of these studies are shown in Figure 1. [0220] Data in Figure 1 is presented as fold-change in cell survival compared to that observed in control.
- anti-TMEM106B antibodies of the present disclosure were effective at maintaining cell viability following SARS-CoV-2 virus infection, indicating that the anti-TMEM106B antibodies of the present disclosure were effective at reducing viral cytopathic effect.
- anti- TMEM106B antibodies TM3, TM11, TM24, TM32, TM34, TM39, TM42, TM51, TM63, TM65, TM71, and TM84 showed approximately 1.5-fold or greater cell survival compared to that observed in virus- infected control cells.
- anti-TMEM106B antibodies TM11, TM24, TM32, and TM51 showed approximately 2-fold or greater cell survival compared to that observed in virus-infected control cells.
- Epitope binning of certain anti-TMEM106B antibodies of the present disclosure was performed by Carterra (Salt Lake City, Nevada, USA) using a pre-mix epitope binning approach. Monoclonal anti-TMEM106B antibodies were immobilized to a CMD 50M chip (Xantec # SPMXCMD50M lot# SCCMD50M0416). The running buffer was HBS-EP+ with lmg/mL BSA.
- the GST-TMEM106B (truncated, comprising amino acids 122-210 of SEQ ID NO: 1) antigen was prepared at a final concentration of 55nM (corresponding to 2pg/mL) and mixed with the competing analyte anti-TMEM106B antibodies at a final concentration of 333nM (corresponding to 50pg/mL) or compared to a buffer control. Samples were injected for 5 minutes over the array and regenerated after every cycle with 1 minute of two parts Pierce IgG-Elution buffer (ThermoFisher Cat#21004) and 1 part of lOmM Glycine, pH 2.0 (Carterra).
- Anti-TMEM106B antibodies sorted into various competing bins and resulting binning profiles. Certain anti-TMEM106B antibodies displayed no ability to block the binding to any of the other anti-TMEM106B antibodies due to their inability to bind the truncated GST-TMEM106B fusion protein used in these binning experiments, indicated that these anti-TMEM106B antibodies bound to the C- terminal domain of TMEM106B; these anti-TMEM106B antibodies were assigned to Bin 5 (see Table 7 below). Other anti-TMEM106B antibodies displayed binning profiles identified as Bin 1 and Bin 2. Bin 2 showed two closely related sub-bins (Bin 3 and Bin 4). Antibodies within Bin 3 or Bin 4 partially block Bin 2 antibodies.
- the GST-TMEM106B (truncated) antigen was prepared at a final concentration of 55nM (corresponding to 2pg/ml) and mixed with the competing analyte anti-TMEM106B antibodies at a final concentration of 333nM (corresponding to 50pg/ml) or compared to a buffer control. Samples were injected for 5 minutes over the array and regenerated after every cycle with 1 minute of two parts Pierce IgG-Elution buffer (ThermoFisher Cat#21004) and 1 part of lOmM Glycine, pH 2.0 (Carterra). See Table 7 below.
- anti-TMEM106B antibodies of the present disclosure bin to different communities (e.g., anti-TMEM106B antibodies that bin to a particular community bind to the same or overlapping epitope), based on the assays used as described above.
- EXAMPLE 5 Effect of anti-TMEM106B antibodies on cytopathic effect (CPE) following SARS-Co V-2 infection in vitro
- Anti-TMEM106B antibodies of the present disclosure were tested for their ability to affect cell viability and CPE in vitro as follows. NCI-H1975 cells (human lung epithelial cells) were plated in RPMI media containing 8% heat-inactivated FBS in 96-well plates at a cell density of 4xl0 4 cells/ml (100 m ⁇ per well). Anti-TMEM106B antibodies were serially diluted (see below for final antibody concentrations) and added to each of the wells; the cells were incubated in the presence of anti- TMEM106B antibodies overnight.
- SARS-CoV-2 virus (SARS-CoV-2 Belgium p625-1) was added to the cells; final serially diluted antibody concentrations following virus addition to the wells was 20,000 ng/ml, 2,000 ng/ml, 200 ng/ml, and 20 ng/ml.
- the cells were then incubated in the presence of anti-TMEM106B antibodies and SARS-CoV-2 virus for three days. Cells were visually observed for cytopathic effect (CPE) induced by the virus and the effect of anti-TMEM106B antibodies thereon. Cell viability was assessed by MTS assay, a colormetric method for determining cell viability.
- CPE cytopathic effect
- the anti-viral compound remdesivir (1 mM) was used as a positive control known to inhibit SARS-CoV-2 induced CPE in NCI-H1975 cells.
- Hamster anti-SARS-CoV-2 antisera was also used as a positive control in these experiments. These experiments were preformed independently twice.
- Figures 2A-2C show that anti-TMEM106B antibodies of the present disclosure were at least as effective as Remdesivir at reducing virus cytopathic effect (as measured by cell viability) in SARS- CoV-2 infected NCI-H1975 human lung epithelial cells.
- anti-TMEM106B antibodies TM3, TM9, TM10, TM11, TM18, TM19, TM21, TM24, TM25, TM28, TM29, TM30, TM32, TM35, TM37, TM48, TM56, TM59, TM60, TM61, TM63, TM64,TM72, TM76, TM78, TM80, TM86, and TM88 resulted in approximately 80% or greater cell viability comparted to percent cell viability in the absence of virus addition.
- EXAMPLE 6 Correlation between an ti- TMEM106B antibody epitope bin and protection front SARS- CoV-2 coronavirus cytopathic effect
- anti-TMEM106B antibodies that belong to bin 2 were effective at preventing virus cytopathic effect (as measured by cell death), whereas anti- TMEM106B antibodies belonging to bin 1 or bin 5 were not.
- anti-TMEM106B antibodies belonging to bins 2, 3 and 4 provided greater than 50% protection against cytopathic effect associated with coronavirus infection.
- the majority of anti-TMEM106B antibodies belonging to bins 2, 3, and 4 showed greater than 80% protection against cytopathic effect upon coronavirus infection (TM-25, TM-32, TM30, TM18, TM19, TM3, TM9, TM12, TM60, TM61, TM11, TM21, TM10, TM72, TM29, TM59, TM78, TM86, TM35, TM37, TM56, TM24, TM48, TM63, TM64, TM76, TM28, TM72, and TM13).
- EXAMPLE 7 Dose titration of anti-TMEM106B antibodies on SARS-Co V-2 infection [0231] NCI-H1975 cells were treated with four different concentrations of anti-TMEM106B antibodies of the present disclosure (20 pg/m L. 2 pg/mL, 0.2 pg/mL, and 0.02 pg/mL) or remdesivir overnight before being infected with SARS-CoV-2 virus for 3 days. At the end of the experiment, cytopathic effects were assessed visually, and cell viability was measured by MTS assay. Cell viability is normalized to cell viability observed in untreated/uninfected cells is shown in Figures 3A-D. As shown in Figures 3A-D, certain anti-TMEM106B antibodies of the present disclosure were effective reducing cytopathic effects associated with SARS-CoV-2 infection in vitro at concentrations as low as 200 ng/mL.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023558349A JP2024511610A (en) | 2021-03-23 | 2022-03-23 | Anti-TMEM106B antibody for treatment and prevention of coronavirus infection |
US18/551,963 US20240166738A1 (en) | 2021-03-23 | 2022-03-23 | Anti-tmem106b antibodies for treating and preventing coronavirus infections |
CN202280023588.5A CN117157321A (en) | 2021-03-23 | 2022-03-23 | anti-TMEM 106B antibodies for the treatment and prevention of coronavirus infection |
EP22716643.6A EP4314063A1 (en) | 2021-03-23 | 2022-03-23 | Anti-tmem106b antibodies for treating and preventing coronavirus infections |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163164873P | 2021-03-23 | 2021-03-23 | |
US63/164,873 | 2021-03-23 | ||
US202163239498P | 2021-09-01 | 2021-09-01 | |
US63/239,498 | 2021-09-01 | ||
US202263318068P | 2022-03-09 | 2022-03-09 | |
US63/318,068 | 2022-03-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022204274A1 true WO2022204274A1 (en) | 2022-09-29 |
Family
ID=81308318
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2022/021533 WO2022204274A1 (en) | 2021-03-23 | 2022-03-23 | Anti-tmem106b antibodies for treating and preventing coronavirus infections |
Country Status (4)
Country | Link |
---|---|
US (1) | US20240166738A1 (en) |
EP (1) | EP4314063A1 (en) |
JP (1) | JP2024511610A (en) |
WO (1) | WO2022204274A1 (en) |
Citations (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
US4301144A (en) | 1979-07-11 | 1981-11-17 | Ajinomoto Company, Incorporated | Blood substitute containing modified hemoglobin |
US4496689A (en) | 1983-12-27 | 1985-01-29 | Miles Laboratories, Inc. | Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer |
US4640835A (en) | 1981-10-30 | 1987-02-03 | Nippon Chemiphar Company, Ltd. | Plasminogen activator derivatives |
US4670417A (en) | 1985-06-19 | 1987-06-02 | Ajinomoto Co., Inc. | Hemoglobin combined with a poly(alkylene oxide) |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US4791192A (en) | 1986-06-26 | 1988-12-13 | Takeda Chemical Industries, Ltd. | Chemically modified protein with polyethyleneglycol |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
EP0404097A2 (en) | 1989-06-22 | 1990-12-27 | BEHRINGWERKE Aktiengesellschaft | Bispecific and oligospecific, mono- and oligovalent receptors, production and applications thereof |
WO1993001161A1 (en) | 1991-07-11 | 1993-01-21 | Pfizer Limited | Process for preparing sertraline intermediates |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
EP0546073A1 (en) | 1990-08-29 | 1993-06-16 | Genpharm Int | Transgenic non-human animals capable of producing heterologous antibodies. |
WO1993016185A2 (en) | 1992-02-06 | 1993-08-19 | Creative Biomolecules, Inc. | Biosynthetic binding protein for cancer marker |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5545807A (en) | 1988-10-12 | 1996-08-13 | The Babraham Institute | Production of antibodies from transgenic animals |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
WO1997011971A1 (en) | 1995-09-28 | 1997-04-03 | Alexion Pharmaceuticals, Inc. | Porcine cell interaction proteins |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
US5648237A (en) | 1991-09-19 | 1997-07-15 | Genentech, Inc. | Expression of functional antibody fragments |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US5739277A (en) | 1995-04-14 | 1998-04-14 | Genentech Inc. | Altered polypeptides with increased half-life |
US5750373A (en) | 1990-12-03 | 1998-05-12 | Genentech, Inc. | Enrichment method for variant proteins having altered binding properties, M13 phagemids, and growth hormone variants |
US5766886A (en) | 1991-12-13 | 1998-06-16 | Xoma Corporation | Modified antibody variable domains |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5789199A (en) | 1994-11-03 | 1998-08-04 | Genentech, Inc. | Process for bacterial production of polypeptides |
US5821337A (en) | 1991-06-14 | 1998-10-13 | Genentech, Inc. | Immunoglobulin variants |
US5840523A (en) | 1995-03-01 | 1998-11-24 | Genetech, Inc. | Methods and compositions for secretion of heterologous polypeptides |
US5869619A (en) | 1991-12-13 | 1999-02-09 | Xoma Corporation | Modified antibody variable domains |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US5959177A (en) | 1989-10-27 | 1999-09-28 | The Scripps Research Institute | Transgenic plants expressing assembled secretory antibodies |
WO1999058572A1 (en) | 1998-05-08 | 1999-11-18 | Cambridge University Technical Services Limited | Binding molecules derived from immunoglobulins which do not trigger complement mediated lysis |
US6040498A (en) | 1998-08-11 | 2000-03-21 | North Caroline State University | Genetically engineered duckweed |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6133426A (en) | 1997-02-21 | 2000-10-17 | Genentech, Inc. | Humanized anti-IL-8 monoclonal antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6248516B1 (en) | 1988-11-11 | 2001-06-19 | Medical Research Council | Single domain ligands, receptors comprising said ligands methods for their production, and use of said ligands and receptors |
US6420548B1 (en) | 1999-10-04 | 2002-07-16 | Medicago Inc. | Method for regulating transcription of foreign genes |
US20020164328A1 (en) | 2000-10-06 | 2002-11-07 | Toyohide Shinkawa | Process for purifying antibody |
US20030115614A1 (en) | 2000-10-06 | 2003-06-19 | Yutaka Kanda | Antibody composition-producing cell |
US20030157108A1 (en) | 2001-10-25 | 2003-08-21 | Genentech, Inc. | Glycoprotein compositions |
US20040093621A1 (en) | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
US20040109865A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Antibody composition-containing medicament |
US20040110704A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells of which genome is modified |
US20040110282A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells in which activity of the protein involved in transportation of GDP-fucose is reduced or lost |
US20040132140A1 (en) | 2002-04-09 | 2004-07-08 | Kyowa Hakko Kogyo Co., Ltd. | Production process for antibody composition |
US6982321B2 (en) | 1986-03-27 | 2006-01-03 | Medical Research Council | Altered antibodies |
US20060025576A1 (en) | 2000-04-11 | 2006-02-02 | Genentech, Inc. | Multivalent antibodies and uses therefor |
US7041870B2 (en) | 2000-11-30 | 2006-05-09 | Medarex, Inc. | Transgenic transchromosomal rodents for making human antibodies |
US7087409B2 (en) | 1997-12-05 | 2006-08-08 | The Scripps Research Institute | Humanization of murine antibody |
US7125978B1 (en) | 1999-10-04 | 2006-10-24 | Medicago Inc. | Promoter for regulating expression of foreign genes |
US7189826B2 (en) | 1997-11-24 | 2007-03-13 | Institute For Human Genetics And Biochemistry | Monoclonal human natural antibodies |
US20070061900A1 (en) | 2000-10-31 | 2007-03-15 | Murphy Andrew J | Methods of modifying eukaryotic cells |
US20070148167A1 (en) | 2005-02-14 | 2007-06-28 | Strohl William R | Non-immunostimulatory antibody and compositions containing the same |
WO2007106585A1 (en) | 2006-03-15 | 2007-09-20 | Alexion Pharmaceuticals, Inc. | Treatment of paroxysmal nocturnal hemoglobinuria patients by an inhibitor of complement |
US20070292936A1 (en) | 2006-05-09 | 2007-12-20 | Genentech, Inc. | Binding polypeptides with optimized scaffolds |
US20080069820A1 (en) | 2006-08-30 | 2008-03-20 | Genentech, Inc. | Multispecific antibodies |
WO2008079246A2 (en) | 2006-12-21 | 2008-07-03 | Medarex, Inc. | Cd44 antibodies |
US20090002360A1 (en) | 2007-05-25 | 2009-01-01 | Innolux Display Corp. | Liquid crystal display device and method for driving same |
US7527791B2 (en) | 2004-03-31 | 2009-05-05 | Genentech, Inc. | Humanized anti-TGF-beta antibodies |
WO2009089004A1 (en) | 2008-01-07 | 2009-07-16 | Amgen Inc. | Method for making antibody fc-heterodimeric molecules using electrostatic steering effects |
WO2013026833A1 (en) | 2011-08-23 | 2013-02-28 | Roche Glycart Ag | Bispecific t cell activating antigen binding molecules |
WO2019133512A1 (en) | 2017-12-29 | 2019-07-04 | Alector Llc | Anti-tmem106b antibodies and methods of use thereof |
-
2022
- 2022-03-23 WO PCT/US2022/021533 patent/WO2022204274A1/en active Application Filing
- 2022-03-23 JP JP2023558349A patent/JP2024511610A/en active Pending
- 2022-03-23 US US18/551,963 patent/US20240166738A1/en active Pending
- 2022-03-23 EP EP22716643.6A patent/EP4314063A1/en active Pending
Patent Citations (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
US4301144A (en) | 1979-07-11 | 1981-11-17 | Ajinomoto Company, Incorporated | Blood substitute containing modified hemoglobin |
US4640835A (en) | 1981-10-30 | 1987-02-03 | Nippon Chemiphar Company, Ltd. | Plasminogen activator derivatives |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4496689A (en) | 1983-12-27 | 1985-01-29 | Miles Laboratories, Inc. | Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer |
US4670417A (en) | 1985-06-19 | 1987-06-02 | Ajinomoto Co., Inc. | Hemoglobin combined with a poly(alkylene oxide) |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US6982321B2 (en) | 1986-03-27 | 2006-01-03 | Medical Research Council | Altered antibodies |
US4791192A (en) | 1986-06-26 | 1988-12-13 | Takeda Chemical Industries, Ltd. | Chemically modified protein with polyethyleneglycol |
US5545807A (en) | 1988-10-12 | 1996-08-13 | The Babraham Institute | Production of antibodies from transgenic animals |
US6248516B1 (en) | 1988-11-11 | 2001-06-19 | Medical Research Council | Single domain ligands, receptors comprising said ligands methods for their production, and use of said ligands and receptors |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693762A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693761A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Polynucleotides encoding improved humanized immunoglobulins |
EP0404097A2 (en) | 1989-06-22 | 1990-12-27 | BEHRINGWERKE Aktiengesellschaft | Bispecific and oligospecific, mono- and oligovalent receptors, production and applications thereof |
US6417429B1 (en) | 1989-10-27 | 2002-07-09 | The Scripps Research Institute | Transgenic plants expressing assembled secretory antibodies |
US5959177A (en) | 1989-10-27 | 1999-09-28 | The Scripps Research Institute | Transgenic plants expressing assembled secretory antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
EP0546073A1 (en) | 1990-08-29 | 1993-06-16 | Genpharm Int | Transgenic non-human animals capable of producing heterologous antibodies. |
US5750373A (en) | 1990-12-03 | 1998-05-12 | Genentech, Inc. | Enrichment method for variant proteins having altered binding properties, M13 phagemids, and growth hormone variants |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
US5821337A (en) | 1991-06-14 | 1998-10-13 | Genentech, Inc. | Immunoglobulin variants |
WO1993001161A1 (en) | 1991-07-11 | 1993-01-21 | Pfizer Limited | Process for preparing sertraline intermediates |
US5648237A (en) | 1991-09-19 | 1997-07-15 | Genentech, Inc. | Expression of functional antibody fragments |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
US5869619A (en) | 1991-12-13 | 1999-02-09 | Xoma Corporation | Modified antibody variable domains |
US5766886A (en) | 1991-12-13 | 1998-06-16 | Xoma Corporation | Modified antibody variable domains |
WO1993016185A2 (en) | 1992-02-06 | 1993-08-19 | Creative Biomolecules, Inc. | Biosynthetic binding protein for cancer marker |
US5789199A (en) | 1994-11-03 | 1998-08-04 | Genentech, Inc. | Process for bacterial production of polypeptides |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US5840523A (en) | 1995-03-01 | 1998-11-24 | Genetech, Inc. | Methods and compositions for secretion of heterologous polypeptides |
US5739277A (en) | 1995-04-14 | 1998-04-14 | Genentech Inc. | Altered polypeptides with increased half-life |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
WO1997011971A1 (en) | 1995-09-28 | 1997-04-03 | Alexion Pharmaceuticals, Inc. | Porcine cell interaction proteins |
US6133426A (en) | 1997-02-21 | 2000-10-17 | Genentech, Inc. | Humanized anti-IL-8 monoclonal antibodies |
US7189826B2 (en) | 1997-11-24 | 2007-03-13 | Institute For Human Genetics And Biochemistry | Monoclonal human natural antibodies |
US7087409B2 (en) | 1997-12-05 | 2006-08-08 | The Scripps Research Institute | Humanization of murine antibody |
WO1999058572A1 (en) | 1998-05-08 | 1999-11-18 | Cambridge University Technical Services Limited | Binding molecules derived from immunoglobulins which do not trigger complement mediated lysis |
US6040498A (en) | 1998-08-11 | 2000-03-21 | North Caroline State University | Genetically engineered duckweed |
US7125978B1 (en) | 1999-10-04 | 2006-10-24 | Medicago Inc. | Promoter for regulating expression of foreign genes |
US6420548B1 (en) | 1999-10-04 | 2002-07-16 | Medicago Inc. | Method for regulating transcription of foreign genes |
US20060025576A1 (en) | 2000-04-11 | 2006-02-02 | Genentech, Inc. | Multivalent antibodies and uses therefor |
US20030115614A1 (en) | 2000-10-06 | 2003-06-19 | Yutaka Kanda | Antibody composition-producing cell |
US20020164328A1 (en) | 2000-10-06 | 2002-11-07 | Toyohide Shinkawa | Process for purifying antibody |
US20070061900A1 (en) | 2000-10-31 | 2007-03-15 | Murphy Andrew J | Methods of modifying eukaryotic cells |
US7041870B2 (en) | 2000-11-30 | 2006-05-09 | Medarex, Inc. | Transgenic transchromosomal rodents for making human antibodies |
US20030157108A1 (en) | 2001-10-25 | 2003-08-21 | Genentech, Inc. | Glycoprotein compositions |
US20040093621A1 (en) | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
US20040110282A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells in which activity of the protein involved in transportation of GDP-fucose is reduced or lost |
US20040110704A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells of which genome is modified |
US20040109865A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Antibody composition-containing medicament |
US20040132140A1 (en) | 2002-04-09 | 2004-07-08 | Kyowa Hakko Kogyo Co., Ltd. | Production process for antibody composition |
US7527791B2 (en) | 2004-03-31 | 2009-05-05 | Genentech, Inc. | Humanized anti-TGF-beta antibodies |
US20070148167A1 (en) | 2005-02-14 | 2007-06-28 | Strohl William R | Non-immunostimulatory antibody and compositions containing the same |
WO2007106585A1 (en) | 2006-03-15 | 2007-09-20 | Alexion Pharmaceuticals, Inc. | Treatment of paroxysmal nocturnal hemoglobinuria patients by an inhibitor of complement |
US20070292936A1 (en) | 2006-05-09 | 2007-12-20 | Genentech, Inc. | Binding polypeptides with optimized scaffolds |
US20080069820A1 (en) | 2006-08-30 | 2008-03-20 | Genentech, Inc. | Multispecific antibodies |
WO2008079246A2 (en) | 2006-12-21 | 2008-07-03 | Medarex, Inc. | Cd44 antibodies |
US20090002360A1 (en) | 2007-05-25 | 2009-01-01 | Innolux Display Corp. | Liquid crystal display device and method for driving same |
WO2009089004A1 (en) | 2008-01-07 | 2009-07-16 | Amgen Inc. | Method for making antibody fc-heterodimeric molecules using electrostatic steering effects |
WO2013026833A1 (en) | 2011-08-23 | 2013-02-28 | Roche Glycart Ag | Bispecific t cell activating antigen binding molecules |
WO2019133512A1 (en) | 2017-12-29 | 2019-07-04 | Alector Llc | Anti-tmem106b antibodies and methods of use thereof |
Non-Patent Citations (91)
Title |
---|
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO. |
"Uniprot", Database accession no. Q9NUM4 |
ABDICHE ET AL., ANALYTICAL BIOCHEMISTRY, vol. 386, 2009, pages 172 - 180 |
ALEGRE ET AL., TRANSPLANTATION, vol. 57, 1994, pages 1537 - 1543 |
ALMAGROFRANSSON, FRONT. BIOSCI., vol. 13, 2008, pages 161 9 - 1633 |
ANGAL ET AL., MOL IMMUNOL., vol. 30, 1993, pages 105 - 108 |
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPENCOTT WILLIAMS AND WILKINS |
ARMOUR ET AL., EUR J IMMUNOL, vol. 29, 1999, pages 2613 - 2624 |
ARMOUR ET AL., MOLECULAR IMMUNOLOGY, vol. 40, 2003, pages 585 - 593 |
ARMOUR ET AL., THE HAEMATOLOGY JOURNAL, 2000, pages 27 |
ARMOUR, IMMUNOLOGY, vol. 40, 2003, pages 585 - 593 |
BACA ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 10678 - 10684 |
BAGGEN ET AL., BIORXIV, DOI:10.1101/2020.09.28.316281, 2020 |
BAGGEN ET AL., NATURE GENETICS, DOI .ORG/10.1038/S41588-021-00805-2, 2021 |
BAGGEN JIM ET AL: "Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2", NATURE GENETICS, NATURE PUBLISHING GROUP US, NEW YORK, vol. 53, no. 4, 8 March 2021 (2021-03-08), pages 435 - 444, XP037659362, ISSN: 1061-4036, [retrieved on 20210308], DOI: 10.1038/S41588-021-00805-2 * |
BARBAS ET AL., PROC NAT. ACAD. SCI. USA, vol. 91, 1994, pages 3809 - 3813 |
BOERNER ET AL., J. IMMUNOL., vol. 147, 1991, pages 60 |
BOLT S ET AL., EUR JLMMUNOL, vol. 23, 1993, pages 403 - 411 |
BRADY ET AL., HUMAN MOLECULAR GENETICS, vol. 126, 2013, pages 696 - 698 |
BROOKS, CURRENT DRUG DISCOVERY TECHNOLOGY, vol. 11, 2014, pages 109 - 112 |
CARTER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 89, 1992, pages 4285 |
CHEN ET AL., J. MOL. BIOL., vol. 293, 1999, pages 865 - 881 |
CHEN-PLOTKIN ET AL., J NEUROSCI, vol. 32, 2012, pages 11213 - 11227 |
CHEUNG ET AL., VIROLOGY, vol. 176, 1990, pages 546 - 552 |
CHOTHIALESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917 |
CHU ET AL., MOL IMMUNOL, vol. 45, 2008, pages 3926 - 3933 |
CLAYTON ET AL., BRAIN, vol. 141, no. 12, 2018, pages 3428 - 3442 |
COLE ET AL., TRANSPLANTATION, vol. 68, 1999, pages 563 - 571 |
DUCRY, BIOCONJUGATE CHEMISTRY, vol. 21, no. 1, 2010, pages 5 - 13 |
EVANS ET AL., J. MED. CHEM., vol. 30, 1987, pages 1229 |
FAUCHERE, J., ADV. DRUG RES., vol. 15, 1986, pages 29 |
FELLOUSE, PROC. NATL. ACAD. SCI. USA, vol. 101, no. 34, 2004, pages 12467 - 12472 |
GERNGROSS, NAT. BIOTECH., vol. 22, 2004, pages 1409 - 1414 |
GRAHAM ET AL., J. GEN VIROL., vol. 36, 1977, pages 59 |
GRIFFITHS ET AL., EMBO J., vol. 12, 1993, pages 725 - 734 |
GRUBER ET AL., J. IMMUNOL., vol. 152, 1994, pages 5368 |
HOLLINGER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 6444 - 6448 |
HOOGENBOOM ET AL., J. MOL. BIOL., vol. 227, 1992, pages 381 - 388 |
HUDSON ET AL., NAT. MED., vol. 9, 2003, pages 129 - 134 |
JACKSON ET AL., J. IMMUNOL., vol. 154, no. 7, 1995, pages 3310 - 2004 |
KANDA ET AL., BIOTECHNOL. BIOENG., vol. 94, no. 4, 2006, pages 680 - 688 |
KIBBE ET AL.: "Handbook of Pharmaceutical Excipients", 2000, PHARMACEUTICAL PRESS |
KIRKLAND ET AL., J. IMMUNOL., vol. 137, 1986, pages 3614 - 3619 |
KOZBOR J., IMMUNOL, vol. 133, 1984, pages 3001 |
KYTE ET AL., J. MOL. BIOL., vol. 157, 1982, pages 105 - 131 |
LANG ET AL., J BIOL CHEM, vol. 287, 2012, pages 19355 - 19365 |
LAZAR ET AL., PROC NATL ACAD SCI USA, vol. 103, 2006, pages 4005 - 4010 |
LEE ET AL., J. IMMUNOL. METHODS, vol. 284, no. 2, 2004, pages 1 19 - 132 |
LI ET AL., NAT. BIOTECH., vol. 24, 2006, pages 210 - 215 |
LI ET AL., PROC. NATL. ACAD. SCI. USA, vol. 1, no. 03, 2006, pages 3557 - 3562 |
LIGHTLE ET AL., PROTEIN SCI., vol. 19, 2010, pages 753 - 762 |
LONBERG, CURR. OPIN. IMMUNOL., vol. 20, 2008, pages 450 - 459 |
MARKS ET AL., BIO/TECHNOLOGY, vol. 10, 1992, pages 779 - 783 |
MATHER ET AL., ANNALS N.Y. ACAD. SCI., vol. 383, 1982, pages 44 - 68 |
MATHER, BIOL. REPROD., vol. 23, 1980, pages 243 - 251 |
MCEARCHERN ET AL., BLOOD, vol. 109, 2007, pages 1185 - 1192 |
MILSTEINCUELLO, NATURE, vol. 305, 1983, pages 537 |
MOLDENHAUER ET AL., SCAND. J. IMMUNOL., vol. 32, 1990, pages 77 - 82 |
MOREL ET AL., MOLEC. IMMUNOL., vol. 25, 1988, pages 7 - 15 |
NICHOLSONRADEMAKERS, ACTA NEUROPATHOL, vol. 132, 2016, pages 639 - 651 |
OKAZAKI ET AL., J. MOL. BIOL., vol. 336, no. 5, 2004, pages 1239 - 1249 |
PETERS ET AL., JBIOL CHEM., vol. 287, no. 29, 2012, pages 24525 - 33 |
PRESTA ET AL., J. IMMUNOL., vol. 151, 1993, pages 2623 |
PROC NATL ACAD SCI USA, vol. 92, 1995, pages 11980 - 11984 |
REDDY ET AL., J. IMMUNOLOGY, vol. 164, 2000, pages 1925 - 1933 |
REDDY ET AL., JLMMUNOL, vol. 164, 2000, pages 1925 - 1933 |
RIPKA ET AL., ARCH. BIOCHEM. BIOPHYS., vol. 249, 1986, pages 533 - 545 |
RIZOGIERASCH, ANN. REV. BIOCHEM., vol. 61, 1992, pages 387 |
ROSOK ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 22611 - 22618 |
SAZINSKY ET AL., PROC NATL ACAD SCI USA 2008, vol. 105, 2008, pages 20167 - 20172 |
SAZINSKY ET AL., PROC NATL ACAD SCI USA, vol. 105, 2008, pages 20167 - 20172 |
SCHIER ET AL., GENE, vol. 169, 1995, pages 147 - 155 |
SCHWENK ET AL., EMBO J, vol. 33, 2014, pages 450 - 467 |
SHIELDS ET AL., R. J. BIOL. CHEM., vol. 276, 2001, pages 6591 - 6604 |
STAHLI ET AL., METHODS IN ENZYMOLOGY, vol. 9, 1983, pages 242 - 253 |
TRAUNECKER ET AL., EMBO J., vol. 10, pages 3655 |
URLAUB ET AL., PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216 |
VAN DIJK ET AL., CURR. OPIN. PHARMACOL., vol. 5, 2001, pages 368 - 74 |
VOLLMERS ET AL., HISTOLOGY AND HISTOPATHOLOGY, vol. 20, no. 3, 2005, pages 927 - 937 |
VOLLMERS ET AL., METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY, vol. 27, no. 3, 2005, pages 185 - 91 |
WANG ET AL., BIORXIV, 2020 |
WANG ET AL., BIORXIV, DOI: 10.1101/2020/09.24.312298, 2020 |
WANG ET AL., CELL, vol. 184, 2021, pages 1 - 14 |
WANG RUOFAN ET AL: "Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses", CELL, ELSEVIER, AMSTERDAM NL, vol. 184, no. 1, 9 December 2020 (2020-12-09), pages 106, XP086441581, ISSN: 0092-8674, [retrieved on 20201209], DOI: 10.1016/J.CELL.2020.12.004 * |
WHITE ET AL., CANCER CELL, vol. 27, 2015, pages 138 - 148 |
WILSON ET AL., CANCER CELL, vol. 19, 2011, pages 101 - 113 |
WINTER ET AL., ANN. REV. IMMUNOL., vol. 12, 1994, pages 433 - 455 |
XU ET AL., CELL IMMUNOL, vol. 200, 2000, pages 16 - 26 |
YAMANE-OHNUKI ET AL., BIOTECH. BIOENG., vol. 87, 2004, pages 614 |
YAZAKIWU: "Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus", vol. 248, 2003, HUMANA PRESS, pages: 255 - 268 |
ZAPATA ET AL., PROTEIN ENG., vol. 8, no. 10, 1995, pages 1057 - 1062 |
Also Published As
Publication number | Publication date |
---|---|
EP4314063A1 (en) | 2024-02-07 |
US20240166738A1 (en) | 2024-05-23 |
JP2024511610A (en) | 2024-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11472874B2 (en) | Anti-MS4A4A antibodies and methods of use thereof | |
US11897968B2 (en) | Anti-MerTK antibodies and methods of use thereof | |
US20240294650A1 (en) | Anti-mertk antibodies and methods of use thereof | |
US11667699B2 (en) | Anti-MS4A4A antibodies and methods of use thereof | |
JP7490565B2 (en) | Anti-TMEM106B antibodies and methods of use thereof | |
US20220380455A1 (en) | Anti-ms4a6a antibodies and methods of use thereof | |
US20240279341A1 (en) | Bispecific anti-mertk and anti-pdl1 antibodies and methods of use thereof | |
US20240279358A1 (en) | Monovalent anti-mertk antibodies and methods of use thereof | |
US20240166738A1 (en) | Anti-tmem106b antibodies for treating and preventing coronavirus infections | |
US20240254227A1 (en) | Anti-CD300LB Antibodies and Methods of Use Thereof | |
US20240270866A1 (en) | Anti-SIRP-Alpha Antibodies and Methods of Use Thereof | |
CN117157321A (en) | anti-TMEM 106B antibodies for the treatment and prevention of coronavirus infection | |
EP4308606A1 (en) | Anti-tmem106b antibodies and methods of use thereof | |
WO2024148232A2 (en) | Anti-il18 binding protein antibodies and methods of use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22716643 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023558349 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022716643 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022716643 Country of ref document: EP Effective date: 20231023 |